Animal pest control method

ABSTRACT

Disclosed is a method for protecting an animal from a parasitic invertebrate pest comprising treating an animal orally or by injection with a pesticidally effective amount of a compound of Formula 1, 
     
       
         
         
             
             
         
       
     
     wherein
         R 1  is halogen, C 1 -C 3  haloalkyl or C 1 -C 3  haloalkoxy;   R 2  is H, halogen, C 1 -C 3  alkyl, C 1 -C 3  haloalkyl or cyano;   R 3  is H, halogen, C 1 -C 3  haloalkyl or C 1 -C 3  haloalkoxy;   R 4  is halogen, C 1 -C 3  alkyl, C 1 -C 3  haloalkyl or C 1 -C 3  haloalkoxy;   R 5  is H, CH 3 , C 2 -C 4  alkylcarbonyl, C 2 -C 4  haloalkylcarbonyl, C 2 -C 5  alkoxycarbonyl or CH 2 O(C 1 -C 3  alkyl);   R 6  is C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 3 -C 6  cycloalkyl or C 3 -C 6  halocycloalkyl, each group substituted with one R 7 ; or R 6  is (CH 2 ) m Q;   and Q, R 7 , R 8a  and R 8b  are as defined in the disclosure.

FIELD OF THE INVENTION

This invention relates to a method for protecting an animal from aparasitic pest and parasitic pest infestation.

BACKGROUND OF THE INVENTION

The control of animal parasites in animal health is essential,especially in the areas of food production and companion animals.Existing methods of treatment and parasite control are being compromiseddue to growing resistance to many current commercial parasiticides. Thediscovery of more effective ways to control animal parasites istherefore imperative. In addition, it is advantageous to discover waysto apply pesticides to animals orally or parenterally so as to preventthe possible contamination of humans or the surrounding environment.

PCT Patent Publication WO 05/085216 discloses isoxazoline derivatives ofFormula i as insecticides

wherein, inter alia, each of A¹, A² and A³ are independently C or N; Gis a benzene ring; W is O or S; and X is halogen or C₁-C₆ haloalkyl.

The method of the present invention is not disclosed in thispublication.

SUMMARY OF THE INVENTION

This invention pertains to a method for protecting animals from aparasitic invertebrate pest comprising orally or parenterallyadministering to the animal a pesticidally effective amount of acompound of Formula 1 (including all geometric and steroisomers), anN-oxide or a salt thereof

wherein

-   -   R¹ is halogen, C₁-C₃ haloalkyl or C₁-C₃ haloalkoxy;    -   R² is H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl or cyano;    -   R³ is H, halogen, C₁-C₃ haloalkyl or C₁-C₃ haloalkoxy;    -   R⁴ is halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl or C₁-C₃ haloalkoxy;    -   R⁵ is H, CH₃, C₂-C₄ alkylcarbonyl, C₂-C₄ haloalkylcarbonyl,        C₂-C₅ alkoxycarbonyl or CH₂O(C₁-C₃ alkyl);    -   R⁶ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl or C₃-C₆        halocycloalkyl, each group substituted with one R⁷; or R⁶ is        (CH₂)_(m)Q;    -   Q is a 4- to 6-membered saturated ring containing carbon atoms        and one O or S(O)_(n) as ring members and optionally substituted        with 1 or 2 R^(8a) and one R^(8b);    -   R⁷ is OR⁹, S(O)_(n)R¹⁰ or C(O)NR¹¹R¹²; or R⁷ is pyridine or        thiazole, each optionally substituted with 1 or 2 R¹⁵;    -   each R^(8a) is independently halogen, cyano or C₁-C₂ alkyl;    -   R^(8b) is OR⁹, S(O)_(n)R¹⁰ or C(O)NR¹¹R¹²;    -   R⁹ is H, CHO, C₂-C₄ alkylcarbonyl, C₂-C₄ haloalkylcarbonyl or        C₂-C₅ alkoxycarbonyl; or R⁹ is C₁-C₄ alkyl or C₁-C₄ haloalkyl,        each optionally substituted with one R¹³; or R⁹ is pyridine or        thiazole, each optionally substituted with 1 or 2 R¹⁵;    -   R¹⁰ is C₁-C₄ alkyl or C₁-C₄ haloalkyl, each optionally        substituted with one R¹³; or R¹⁰ is pyridine or thiazole, each        optionally substituted with 1 or 2 R¹⁵;    -   R¹¹ is H, CHO, C₁-C₄ alkyl, C₁-C₄ haloalkyl, CH₂O(C₁-C₃ alkyl),        C₂-C₄ alkylcarbonyl, C₂-C₄ haloalkylcarbonyl or C₂-C₅        alkoxycarbonyl;    -   R¹² is C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₃-C₆ cycloalkyl, each        optionally substituted with one R¹³; or R¹² is H, C₃-C₆ alkenyl,        C₃-C₆ haloalkenyl, C₃-C₆ alkynyl or OR¹⁴;    -   R¹³ is cyano, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, OH, OR¹⁴        or S(O)_(n)R¹⁶; or R¹³ is pyridine or thiazole, each optionally        substituted with 1 or 2 R¹⁵;    -   R¹⁴ is C₁-C₄ alkyl or C₁-C₄ haloalkyl;    -   each R¹⁵ is independently halogen, cyano, C₁-C₃ alkyl, C₁-C₃        haloalkyl or C₁-C₃ haloalkoxy;    -   R¹⁶ is C₁-C₄ alkyl or C₁-C₄ haloalkyl;    -   m is 0 or 1; and    -   n is 0, 1 or 2.

This invention also relates to such method wherein the parasiticinvertebrate pest or its environment is contacted with a compositioncomprising a biologically effective amount of a compound of Formula 1,an N-oxide or a salt thereof, and at least one additional componentselected from the group consisting of surfactants, solid diluents andliquid diluents, said composition optionally further comprising abiologically effective amount of at least one additional biologicallyactive compound or agent.

This invention further provides a method for treating, preventing,inhibiting and/or killing ecto- and/or endoparasites comprisingadministering to and/or on the animal a pesticidally effective amount ofa compound of Formula 1, an N-oxide or a salt thereof, (e.g., as acomposition described herein). This invention also relates to suchmethod wherein a pesticidally effective amount of a compound of Formula1, an N-oxide or a salt thereof, (e.g., as a composition describedherein) is administered to the environment (e.g., a stall or blanket) inwhich an animal resides.

DETAILS OF THE INVENTION

As used herein, the terms “comprises,” “comprising,” “includes,”“including,” “has,” “having,” “contains” or “containing,” or any othervariation thereof, are intended to cover a non-exclusive inclusion. Forexample, a composition, a mixture, process, method, article, orapparatus that comprises a list of elements is not necessarily limitedto only those elements but may include other elements not expresslylisted or inherent to such composition, mixture, process, method,article, or apparatus. Further, unless expressly stated to the contrary,“or” refers to an inclusive or and not to an exclusive or. For example,a condition A or B is satisfied by any one of the following: A is true(or present) and B is false (or not present), A is false (or notpresent) and B is true (or present), and both A and B are true (orpresent).

Also, the indefinite articles “a” and “an” preceding an element orcomponent of the invention are intended to be nonrestrictive regardingthe number of instances (i.e. occurrences) of the element or component.Therefore “a” or “an” should be read to include one or at least one, andthe singular word form of the element or component also includes theplural unless the number is obviously meant to be singular.

As referred to in this disclosure, the terms “pest”, “invertebrate pest”and “parasitic invertebrate pest” include arthropods, gastropods andnematodes of economic importance as pests. The term “arthropod” includesinsects, mites, spiders, scorpions, centipedes, millipedes, pill bugsand symphylans. The term “gastropod” includes snails, slugs and otherStylommatophora. The term “nematode” includes all of the helminths, suchas roundworms, heartworms, and phytophagous nematodes (Nematoda), flukes(Tematoda), Acanthocephala, and tapeworms (Cestoda).

In the context of this disclosure “invertebrate pest control” meansinhibition of invertebrate pest development (including mortality,feeding reduction, and/or mating disruption), and related expressionsare defined analogously. The terms “pesticidal” and “pesticidally” referto observable effects on a pest to provide protection of an animal fromthe pest. Pesticidal effects typically relate to diminishing theoccurrence or activity of the target parasitic invertebrate pest. Sucheffects on the pest include necrosis, death, retarded growth, diminishedmobility or lessened ability to remain on or in the host animal, reducedfeeding and inhibition of reproduction. These effects on parasiticinvertebrate pests provide control (including prevention, reduction orelimination) of parasitic infestation or infection of the animal.

A parasite “infestation” refers to the presence of parasites in numbersthat pose a risk to humans or animals. The infestation can be in theenvironment (e.g., in human or animal housing, bedding, and surroundingproperty or structures), on agricultural crops or other types of plants,or on the skin or fur of an animal. When the infestation is within ananimal (e.g., in the blood or other internal tissues), the terminfestation is also intended to be synonymous with the term “infection”as that term is generally understood in the art, unless otherwisestated.

In the above recitations, the term “alkyl”, used either alone or incompound words such as “haloalkyl” includes straight-chain or branchedalkyls, such as methyl, ethyl, n-propyl, i-propyl, or the differentbutyl, pentyl or hexyl isomers. “Alkenyl” includes straight-chain orbranched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and thedifferent butenyl, pentenyl and hexenyl isomers. “Alkenyl” also includespolyenes such as 1,2-propadienyl and 2,4-hexadienyl. “Alkynyl” includesstraight-chain or branched alkynes such as ethynyl, 1-propynyl,2-propynyl and the different butynyl, pentynyl and hexynyl isomers.“Alkynyl” can also include moieties comprised of multiple triple bondssuch as 2,5-hexadiynyl.

“Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl. The term “cyclopropylmethyl” denotes cyclopropylsubstitution on a methyl moiety.

The term “halogen”, either alone or in compound words such as“haloalkyl”, or when used in descriptions such as “alkyl substitutedwith halogen” includes fluorine, chlorine, bromine or iodine. Further,when used in compound words such as “haloalkyl”, or when used indescriptions such as “alkyl substituted with halogen” said alkyl may bepartially or fully substituted with halogen atoms which may be the sameor different. Examples of “haloalkyl” or “alkyl substituted withhalogen” include CF₃, CH₂Cl, CH₂CF₃ and CCl₂CF₃. The terms“halocycloalkyl”, “haloalkoxy”, “haloalkenyl”, and the like, are definedanalogously to the term “haloalkyl”. Examples of “haloalkoxy” includeOCF₃, OCH₂CCl₃, OCH₂CH₂CHF₂ and OCH₂CF₃. Examples of “haloalkenyl”include CH₂CH═C(Cl)₂ and CH₂CH═CHCH₂CF₃.

“Alkylcarbonyl” denotes a straight-chain or branched alkyl moiety bondedto a C(O) moiety. The chemical abbreviation C(O) as used hereinrepresents a carbonyl moiety. Examples of “alkylcarbonyl” includeC(O)CH₃, C(O)CH₂CH₂CH₃ and C(O)CH(CH₃)₂.

The total number of carbon atoms in a substituent group is indicated bythe “C_(i)-C_(j)” prefix where i and j are numbers from 1 to 6. Forexample, C₁-C₃ alkyl designates methyl through propyl.

When a group contains a substituent which can be hydrogen, for exampleR⁵ or R¹¹, then when this substituent is taken as hydrogen, it isrecognized that this is equivalent to said group being unsubstituted.

The term “ring member”, as used in the definition of the substituent Qin the Summary of the Invention, refers to an atom or other moiety(e.g., O or S(O)_(n)) forming the backbone of a ring. Examples of Qinclude

Compounds of Formula 1 can exist as one or more stereoisomers. Thevarious stereoisomers include enantiomers, diastereomers andatropisomers. One skilled in the art will appreciate that onestereoisomer may be more active and/or may exhibit beneficial effectswhen enriched relative to the other stereoisomer(s) or when separatedfrom the other stereoisomer(s). Additionally, the skilled artisan knowshow to separate, enrich, and/or to selectively prepare saidstereoisomers. The compounds Formula 1 may be present as a mixture ofstereoisomers, individual stereoisomers or as an optically active form.For example, two possible enantiomers of Formula 1 are depicted asFormula 1a and Formula 1b involving the isoxazoline chiral centeridentified with an asterisk (*). Analogously, other chiral centers arepossible at, for example, R¹, R⁶, R⁹ and R¹¹.

Molecular depictions drawn herein follow standard conventions fordepicting stereochemistry. To indicate stereoconfiguration, bonds risingfrom the plane of the drawing and towards the viewer are denoted bysolid wedges wherein the broad end of the wedge is attached to the atomrising from the plane of the drawing towards the viewer. Bonds goingbelow the plane of the drawing and away from the viewer are denoted bydashed wedges wherein the narrow end of the wedge is attached to theatom further away from the viewer. Constant width lines indicate bondswith a direction opposite or neutral relative to bonds shown with solidor dashed wedges; constant width lines also depict bonds in molecules orparts of molecules in which no particular stereoconfiguration isintended to be specified.

The more biologically active enantiomer is believed to be Formula 1a.Formula 1a has the (S) configuration at the chiral carbon, and Formula1b has the (R) configuration at the chiral carbon.

The method of this invention comprises racemic mixtures, for example,equal amounts of the enantiomers of Formulae 1a and 1b. In addition, themethod of this invention includes compounds that are enriched comparedto the racemic mixture in an enantiomer of Formula 1. Also included arethe essentially pure enantiomers of compounds of Formula 1, for example,Formula 1a and Formula 1b.

When enantiomerically enriched, one enantiomer is present in greateramounts than the other, and the extent of enrichment can be defined byan expression of enantiomeric excess (“ee”), which is defined as(2x−1)·100%, where x is the mole fraction of the dominant enantiomer inthe mixture (e.g., an ee of 20% corresponds to a 60:40 ratio ofenantiomers).

Preferably the compositions of Formula 1 have at least a 50%enantiomeric excess; more preferably at least a 75% enantiomeric excess;still more preferably at least a 90% enantiomeric excess; and the mostpreferably at least a 94% enantiomeric excess of the more active isomer.Of particular note are enantiomerically pure embodiments of the moreactive isomer.

Compounds of Formula 1 can comprise additional chiral centers. Themethod of this invention comprises racemic mixtures as well as enrichedand essentially pure stereoconfigurations at these additional chiralcenters. Compounds of Formula 1 can exist as one or more conformationalisomers due to restricted rotation about the amide bond in Formula 1.The method of this invention comprises mixtures of conformationalisomers. In addition, the method of this invention includes compoundsthat are enriched in one conformer relative to others.

Embodiments of the present invention as described in the Summary of theInvention include those described below. In the following Embodiments,reference to “a compound of Formula 1” includes the definitions ofsubstituents specified in the Summary of the Invention unless furtherdefined in the Embodiments.

Embodiment 1

The method described in the Summary of the Invention wherein thepesticidally effective compound is selected from an isoxazoline ofFormula 1 (including all geometric and steroisomers), an N-oxide or asalt thereof

wherein

-   -   R¹ is halogen, C₁-C₃ haloalkyl or C₁-C₃ haloalkoxy;    -   R² is H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl or cyano;    -   R³ is H, halogen, C₁-C₃ haloalkyl or C₁-C₃ haloalkoxy;    -   R⁴ is halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl or C₁-C₃ haloalkoxy;    -   R⁵ is H, CH₃, C₂-C₄ alkylcarbonyl, C₂-C₄ haloalkylcarbonyl,        C₂-C₅ alkoxycarbonyl or CH₂O(C₁-C₃ alkyl);    -   R⁶ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl or C₃-C₆        halocycloalkyl, each group substituted with one R⁷; or R⁶ is        (CH₂)_(m)Q;    -   Q is a 4- to 6-membered saturated ring containing carbon atoms        and one O or S(O)_(n) as ring members and optionally substituted        with 1 or 2 R^(8a) and one R^(8b);    -   R⁷ is OR⁹, S(O)_(n)R¹⁰ or C(O)NR¹¹R¹²; or R⁷ is pyridine or        thiazole, each optionally substituted with 1 or 2 R¹⁵;    -   each R^(8a) is independently halogen, cyano or C₁-C₂ alkyl;    -   R^(8b) is OR⁹, S(O)_(n)R¹⁰ or C(O)NR¹¹R¹²;    -   R⁹ is H, CHO, C₂-C₄ alkylcarbonyl, C₂-C₄ haloalkylcarbonyl or        C₂-C₅ alkoxycarbonyl; or R⁹ is C₁-C₄ alkyl or C₁-C₄ haloalkyl,        each optionally substituted with one R¹³; or R⁹ is pyridine or        thiazole, each optionally substituted with 1 or 2 R¹⁵;    -   R¹⁰ is C₁-C₄ alkyl or C₁-C₄ haloalkyl, each optionally        substituted with one R¹³; or R¹⁰ is pyridine or thiazole, each        optionally substituted with 1 or 2 R¹⁵;    -   R¹¹ is H, CHO, C₁-C₄ alkyl, C₁-C₄ haloalkyl, CH₂O(C₁-C₃ alkyl),        C₂-C₄ alkylcarbonyl, C₂-C₄ haloalkylcarbonyl or C₂-C₅        alkoxycarbonyl; R¹² is C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₃-C₆        cycloalkyl, each optionally substituted with one R¹³; or R¹² is        H, C₃-C₆ alkenyl, C₃-C₆ haloalkenyl, C₃-C₆ alkynyl or OR¹⁴;    -   R¹³ is cyano, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, OH, OR¹⁴        or S(O)_(n)R¹⁶; or R¹³ is pyridine or thiazole, each optionally        substituted with 1 or 2 R¹⁵;    -   R¹⁴ is C₁-C₄ alkyl or C₁-C₄ haloalkyl;    -   each R¹⁵ is independently halogen, cyano, C₁-C₃ alkyl, C₁-C₃        haloalkyl or C₁-C₃ haloalkoxy;    -   R¹⁶ is C₁-C₄ alkyl or C₁-C₄ haloalkyl;    -   m is 0 or 1; and    -   n is 0, 1 or 2.

Embodiment 2

The method of Embodiment 1 wherein R¹ is Cl, Br, CF₃, OCF₃ or OCH₂CF₃.

Embodiment 3

The method of Embodiment 2 wherein R¹ is Cl, Br or CF₃.

Embodiment 4

The method of Embodiment 3 wherein R¹ is Cl.

Embodiment 5

The method of Embodiment 3 wherein R¹ is Br.

Embodiment 6

The method of Embodiment 3 wherein R¹ is CF₃.

Embodiment 7

The method of Embodiment 1 wherein R² is H, F or Cl.

Embodiment 8

The method of Embodiment 7 wherein R² is H.

Embodiment 9

The method of Embodiment 7 wherein R² is F.

Embodiment 10

The method of Embodiment 7 wherein R² is Cl.

Embodiment 11

The method of Embodiment 1 wherein R³ is H, F, Cl, Br or CF₃.

Embodiment 12

The method of Embodiment 11 wherein R³ is H, Cl, Br or CF₃.

Embodiment 13

The method of Embodiment 12 wherein R³ is Cl, Br or CF₃.

Embodiment 14

The method of Embodiment 11 wherein R³ is H.

Embodiment 15

The method of Embodiment 11 wherein R³ is Cl.

Embodiment 16

The method of Embodiment 11 wherein R³ is Br.

Embodiment 17

The method of Embodiment 11 wherein R³ is CF₃.

Embodiment 18

The method of Embodiment 1 wherein R⁴ is halogen or C₁-C₃ alkyl.

Embodiment 19

The method of Embodiment 18 wherein R⁴ is halogen or methyl.

Embodiment 20

The method of Embodiment 19 wherein R⁴ is halogen.

Embodiment 21

The method of Embodiment 20 wherein R⁴ is Cl.

Embodiment 22

The method of Embodiment 19 wherein R⁴ is methyl.

Embodiment 23

The method of Embodiment 1 wherein R⁵ is H.

Embodiment 24

The method of Embodiment 1 wherein R⁶ is halogen or C₁-C₆ alkyl.

Embodiment 25

The method of Embodiment 1 wherein R⁶ is C₁-C₆ alkyl substituted withone R⁷;

Embodiment 26

The method of Embodiment 1 wherein R⁷ is OR⁹, S(O)_(n)R¹⁰ orC(O)NR¹¹R¹².

Embodiment 27

The method of Embodiment 26 wherein R⁷ is OR⁹.

Embodiment 28

The method of Embodiment 26 wherein R⁷ is S(O)_(n)R¹⁰.

Embodiment 29

The method of Embodiment 26 wherein R⁷ is C(O)NR¹¹R¹².

Embodiment 30

The method of Embodiment 1 wherein R⁹ is H or C₁-C₄ alkyl.

Embodiment 31

The method of Embodiment 30 wherein R⁹ is H or methyl.

Embodiment 32

The method of Embodiment 31 wherein R⁹ is H.

Embodiment 33

The method of Embodiment 31 wherein R⁹ is methyl.

Embodiment 34

The method of Embodiment 1 wherein R¹⁰ is C₁-C₄ alkyl.

Embodiment 35

The method of Embodiment 1 wherein R¹¹ is H.

Embodiment 36

The method of Embodiment 1 wherein R¹² is C₁-C₄ alkyl or C₁-C₄haloalkyl, each optionally substituted with one R¹³.

Embodiment 37

The method of Embodiment 1 wherein R¹² is C₁-C₄ alkyl or C₁-C₄haloalkyl.

Embodiment 38

The method of Embodiment 37 wherein R¹² is C₁-C₄ haloalkyl.

Embodiment 38a

The method of Embodiment 1 wherein R¹² is cyclopropyl orcyclopropylmethyl.

Embodiment 39

The method of Embodiment 1 wherein R¹³ is cyano, OH, OR¹⁴ orS(O)_(n)R¹⁶.

Embodiment 40

The method of Embodiment 39 wherein R¹³ is cyano.

Embodiment 41

The method of Embodiment 39 wherein R¹³ is OH.

Embodiment 42

The method of Embodiment 39 wherein R¹³ is OR¹⁴.

Embodiment 43

The method of Embodiment 39 wherein R¹³ is S(O)_(n)R¹⁶.

Embodiment 44

The method of Embodiment 1 wherein the pesticidally effective amount ofa compound of Formula 1 is administered orally.

Embodiment 45

The method of Embodiment 1 wherein the pesticidally effective amount ofa compound of Formula 1 is administered parenterally.

Embodiment 46

The method of Embodiment 45 wherein the pesticidally effective amount ofa compound of Formula 1 is administered by injection.

Embodiment 47

The method of Embodiment 1 wherein the animal to be protected is avertebrate.

Embodiment 48

The method of Embodiment 47 wherein the vertebrate to be protected is amammal, avian or fish.

Embodiment 49

The method of Embodiment 48 wherein the vertebrate to be protected is amammal.

Embodiment 50

The method of Embodiment 48 wherein the vertebrate to be protected is anavian.

Embodiment 51

The method of Embodiment 48 wherein the vertebrate to be protected is afish.

Embodiment 52

The method of Embodiment 49 wherein the mammal to be protected is ahuman.

Embodiment 53

The method of Embodiment 49 wherein the mammal to be protected islivestock.

Embodiment 54

The method of Embodiment 49 wherein the mammal to be protected is acanine.

Embodiment 55

The method of Embodiment 49 wherein the mammal to be protected is afeline.

Embodiment 56

The method of Embodiment 1 wherein the parasitic invertebrate pest is anectoparasite.

Embodiment 57

The method of Embodiment 1 wherein the parasitic invertebrate pest is anendoparasite.

Embodiment 58

The method of Embodiment 1 wherein the parasitic invertebrate pest is anhelminth.

Embodiment 59

The method of Embodiment 1 wherein the parasitic invertebrate pest is anarthropod.

Embodiment 60

The method of Embodiment 1 wherein the parasitic invertebrate pest is afly, mosquito, mite, tick, louse, flea, true bug or maggot.

Embodiment 61

The method of Embodiment 1 wherein the parasitic invertebrate pest is afly, mosquito, mite, tick, louse, flea, bed bug, kissing bug or maggot.

Embodiment 62

The method of Embodiment 61 wherein the parasitic invertebrate pest is afly or maggot.

Embodiment 63

The method of Embodiment 61 wherein the parasitic invertebrate pest is amosquito.

Embodiment 64

The method of Embodiment 61 wherein the parasitic invertebrate pest is atick or mite.

Embodiment 65

The method of Embodiment 61 wherein the parasitic invertebrate pest is alouse.

Embodiment 66

The method of Embodiment 61 wherein the parasitic invertebrate pest is aflea.

Embodiment 67

The method of Embodiment 61 wherein the parasitic invertebrate pest is atrue bug.

Embodiment 68

The method of Embodiment 61 wherein the parasitic invertebrate pest is abed bug or kissing bug.

Embodiment 69

The method of Embodiment 61 wherein the animal to be protected is a cator dog and the parasitic invertebrate pest is a flea, tick or mite.

Embodiment 70

The method of Embodiment 44 wherein the parasiticidally effective amountof a compound of Formula 1 is administered orally two times a year.

Embodiment 71

The method of Embodiment 44 wherein the parasiticidally effective amountof a compound of Formula 1 is administered orally once a month.

Embodiment 72

The method of Embodiment 44 wherein the parasiticidally effective amountof a compound of Formula 1 is administered orally two times a month.

Embodiments of this invention, including Embodiments 1-72 above as wellas any other embodiments described herein, can be combined in anymanner.

Combinations of Embodiments 1-43 are illustrated by:

Embodiment A

The method of Embodiment 1 wherein

-   -   R¹ is Cl, Br or CF₃;    -   R² is H, F or Cl; and    -   R³ is H, Cl, Br or CF₃.

Embodiment B

A method of Embodiment A wherein

-   -   R¹ and R³ are Cl; and    -   R² is H.

Embodiment C

A method of Embodiment A wherein

-   -   R¹ and R³ are Br; and    -   R² is H.

Embodiment D

A method of Embodiment A wherein

-   -   R¹ and R³ are CF₃; and    -   R² is H.

Embodiment E

A method of Embodiment A wherein

-   -   R¹, R² and R³ are Cl.

Embodiment F

A method of Embodiment A wherein

-   -   R¹ and R³ are Cl; and    -   R² is F.

Embodiment G

A method of Embodiment A wherein

-   -   R¹ is CF₃; and    -   R² and R³ are H.

Embodiment H

A method of Embodiment A wherein

-   -   R⁴ is methyl; and    -   R⁵ is H.

Embodiment I

A method of Embodiment A wherein

-   -   R⁵ is H;    -   R⁶ is C₁-C₆ alkyl substituted with one R⁷; and    -   R⁷ is OR⁹, S(O)_(n)R¹⁰ or C(O)NR¹¹R¹².

Embodiment J

A method of Embodiment A wherein

-   -   R⁷ is C(O)NR¹¹R¹²; and    -   R¹² is C₁-C₄ alkyl or C₁-C₄ haloalkyl, each optionally        substituted with one R¹³.

Embodiment K

A method of Embodiment A wherein

-   -   R⁴ is Cl or CH₃;    -   R⁵ is H;    -   R⁶ is C₁-C₆ alkyl substituted with one R⁷; and    -   R⁷ is OR⁹, S(O)₁₁R¹⁰ or C(O)NR¹¹R¹².

Embodiment L

A method of Embodiment K wherein

-   -   R¹ is Cl, Br, CF₃, OCF₃ or OCH₂CF₃;    -   R² is H; and    -   R³ is H, F, Cl, Br or CF₃.

Embodiment M

A method of Embodiment L wherein

-   -   R⁴ is CH₃; and    -   R⁷ is C(O)NR¹¹R¹².

Embodiment N

A method of Embodiment M wherein

-   -   R¹ is CF₃; and    -   R³ is Cl, Br or CF₃.

Embodiment O

A method of Embodiment M wherein

-   -   R¹¹ is H; and    -   R¹² is C₁-C₄ alkyl or C₁-C₄ haloalkyl.

Embodiment P

A method of Embodiment M wherein

-   -   R¹¹ is H; and    -   R¹² is cyclopropyl or cyclopropylmethyl.

Specific embodiments include the method of Embodiment 1 whereincompounds of Formula 1 are selected from the group consisting of:

-   4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(2-pyridinylmethyl)benzamide,-   4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]benzamide,-   4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-[2-(methylthio)ethyl]benzamide,-   4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-[2-(methylsulfinyl)ethyl]benzamide,-   4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-[2-(methylsulfonyl)ethyl]benzamide,    and-   4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-[1-methyl-3-(methylthio)propyl]benzamide.

Further specific embodiments include the method of Embodiment 1 whereincompounds of Formula 1 are selected from Table A and B. The followingabbreviation is used in Table A: c-Pr means cyclopropyl.

TABLE A

R¹ R³ R¹² R^(a) is H Cl Cl CH₃ Cl Cl CH₂CH₃ Cl Cl CH(CH₃)₂ Cl Cl CH₂CF₃Cl Cl c-Pr Cl Cl CH₂—c-Pr Cl CF₃ CH₃ Cl CF₃ CH₂CH₃ Cl CF₃ CH(CH₃)₂ ClCF₃ CH₂CF₃ Cl CF₃ c-Pr Cl CF₃ CH₂—c-Pr Cl OCH₂CF₃ CH₃ Cl OCH₂CF₃ CH₂CH₃Cl OCH₂CF₃ CH(CH₃)₂ Cl OCH₂CF₃ CH₂CF₃ Cl OCH₂CF₃ c-Pr Cl OCH₂CF₃CH₂—c-Pr Br CF₃ CH₃ Br CF₃ CH₂CH₃ Br CF₃ CH(CH₃)₂ Br CF₃ CH₂CF₃ Br CF₃c-Pr Br CF₃ CH₂—c-Pr CF₃ CF₃ CH₃ CF₃ CF₃ CH₂CH₃ CF₃ CF₃ CH(CH₃)₂ CF₃ CF₃CH₂CF₃ CF₃ CF₃ c-Pr CF₃ CF₃ CH₂—c-Pr R^(a) is CH₃ Cl Cl CH₃ Cl Cl CH₂CH₃Cl Cl CH(CH₃)₂ Cl Cl CH₂CF₃ Cl Cl c-Pr Cl Cl CH₂—c-Pr Cl CF₃ CH₃ Cl CF₃CH₂CH₃ Cl CF₃ CH(CH₃)₂ Cl CF₃ CH₂CF₃ Cl CF₃ c-Pr Cl CF₃ CH₂—c-Pr ClOCH₂CF₃ CH₃ Cl OCH₂CF₃ CH₂CH₃ Cl OCH₂CF₃ CH(CH₃)₂ Cl OCH₂CF₃ CH₂CF₃ ClOCH₂CF₃ c-Pr Cl OCH₂CF₃ CH₂—c-Pr Br CF₃ CH₃ Br CF₃ CH₂CH₃ Br CF₃CH(CH₃)₂ Br CF₃ CH₂CF₃ Br CF₃ c-Pr Br CF₃ CH₂—c-Pr CF₃ CF₃ CH₃ CF₃ CF₃CH₂CH₃ CF₃ CF₃ CH(CH₃)₂ CF₃ CF₃ CH₂CF₃ CF₃ CF₃ c-Pr CF₃ CF₃ CH₂—c-Pr

TABLE B

R¹ R³ n R^(b) R^(a) is H Cl Cl 0 CH₃ Cl Cl 1 CH₃ Cl Cl 2 CH₃ Cl Cl 0CH₂CH₃ Cl Cl 1 CH₂CH₃ Cl Cl 2 CH₂CH₃ Cl CF₃ 0 CH₃ Cl CF₃ 1 CH₃ Cl CF₃ 2CH₃ Cl CF₃ 0 CH₂CH₃ Cl CF₃ 1 CH₂CH₃ Cl CF₃ 2 CH₂CH₃ Cl OCH₂CF₃ 0 CH₃ ClOCH₂CF₃ 1 CH₃ Cl OCH₂CF₃ 2 CH₃ Cl OCH₂CF₃ 0 CH₂CH₃ Cl OCH₂CF₃ 1 CH₂CH₃Cl OCH₂CF₃ 2 CH₂CH₃ Br CF₃ 0 CH₃ Br CF₃ 1 CH₃ Br CF₃ 2 CH₃ Br CF₃ 0CH₂CH₃ Br CF₃ 1 CH₂CH₃ Br CF₃ 2 CH₂CH₃ CF₃ CF₃ 0 CH₃ CF₃ CF₃ 1 CH₃ CF₃CF₃ 2 CH₃ CF₃ CF₃ 0 CH₂CH₃ CF₃ CF₃ 1 CH₂CH₃ CF₃ CF₃ 2 CH₂CH₃ R^(a) isCH₃ Cl Cl 0 CH₃ Cl Cl 1 CH₃ Cl Cl 2 CH₃ Cl Cl 0 CH₂CH₃ Cl Cl 1 CH₂CH₃ ClCl 2 CH₂CH₃ Cl CF₃ 0 CH₃ Cl CF₃ 1 CH₃ Cl CF₃ 2 CH₃ Cl CF₃ 0 CH₂CH₃ ClCF₃ 1 CH₂CH₃ Cl CF₃ 2 CH₂CH₃ Cl OCH₂CF₃ 0 CH₃ Cl OCH₂CF₃ 1 CH₃ ClOCH₂CF₃ 2 CH₃ Cl OCH₂CF₃ 0 CH₂CH₃ Cl OCH₂CF₃ 1 CH₂CH₃ Cl OCH₂CF₃ 2CH₂CH₃ Br CF₃ 0 CH₃ Br CF₃ 1 CH₃ Br CF₃ 2 CH₃ Br CF₃ 0 CH₂CH₃ Br CF₃ 1CH₂CH₃ Br CF₃ 2 CH₂CH₃ CF₃ CF₃ 0 CH₃ CF₃ CF₃ 1 CH₃ CF₃ CF₃ 2 CH₃ CF₃ CF₃0 CH₂CH₃ CF₃ CF₃ 1 CH₂CH₃ CF₃ CF₃ 2 CH₂CH₃

The compounds of Formula 1 or any of Embodiments 1-43 or Embodiments A-Pcan be used for the protection of an animal from an invertebrateparasitic pest by oral or parenteral administration of the compound.

Therefore, the invention is understood to include the compounds ofFormula 1 or any of Embodiments 1-43 or Embodiments A-P (andcompositions containing them) for use as an animal medicament, or moreparticularly a parasiticidal animal medicament. The animals to beprotected are as defined in any of Embodiments 47-55. The invertebrateparasitic pests are as defined in any of Embodiments 56-68. Themedicament may be in oral or parenteral dosage forms.

The invention is also understood to include the use of compounds ofFormula 1 or any of Embodiments 1-43 or Embodiments A-P in themanufacture of medicaments for the protection of an animal from a aninvertebrate parasitic pest. The animals to be protected are as definedin any of Embodiments 47-55. The invertebrate parasitic pests are asdefined in any of Embodiments 56-68. The medicament may be in oral orparenteral dosage forms.

The invention is also understood to include compounds of Formula 1 orany of Embodiments 1-43 or Embodiments A-P for use in the manufacture ofmedicaments for the protection of an animal from an invertebrateparasitic pest. The animals to be protected are as defined in any ofEmbodiments 47-55. The invertebrate parasitic pests are as defined inany of Embodiments 56-68. The medicament may be in oral or parenteraldosage forms.

The invention is also understood to include compounds of Formula 1 orany of Embodiments 1-43 or Embodiments A-P packaged and presented forthe protection of an animal from an invertebrate parasitic pest. Theanimals to be protected are as defined in any of Embodiments 47-55. Theinvertebrate parasitic pests are as defined in any of Embodiments 56-68.The compounds of the invention may be packaged and presented as oral orparenteral dosage forms.

The invention is also understood to include a process for manufacturinga composition for protecting an animal from an invertebrate parasiticpest characterized in that a compound of Claim 1 is admixed with atleast one pharmaceutically or veterinarily acceptable carrier. Theanimals to be protected are as defined in any of Embodiments 47-55. Theinvertebrate parasitic pests are as defined in any of Embodiments 56-68.The compositions of the invention may be packaged and presented as oralor parenteral dosage forms.

Isoxazolines of Formula 1 can be prepared as described in PCT PatentPublication WO 2005/085216.

One skilled in the art will appreciate that not all pyridineheterocycles can form N-oxides; one skilled in the art will recognizethose pyridine heterocycles which can form N-oxides. Synthetic methodsfor the preparation of N-oxides of pyridine heterocycles are very wellknown by one skilled in the art including the oxidation of heterocycleswith peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA),hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide,sodium perborate, and dioxiranes such as dimethyldioxirane. Thesemethods for the preparation of N-oxides have been extensively describedand reviewed in the literature, see for example: T. L. Gilchrist inComprehensive Organic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed.,Pergamon Press; M. Tisler and B. Stanovnik in Comprehensive HeterocyclicChemistry, vol. 3, pp 18-20, A. J. Boulton and A. McKillop, Eds.,Pergamon Press; M. R. Grimmett and B. R. T. Keene in Advances inHeterocyclic Chemistry, vol. 43, pp 149-161, A. R. Katritzky, Ed.,Academic Press; M. Tisler and B. Stanovnik in Advances in HeterocyclicChemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J. Boulton, Eds.,Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk in Advancesin Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A.J. Boulton, Eds., Academic Press.

One skilled in the art recognizes that because in the environment andunder physiological conditions salts of chemical compounds are inequilibrium with their corresponding nonsalt forms, salts share thebiological utility of the nonsalt forms. Thus a wide variety of salts ofthe compounds of Formula 1 are useful for control of invertebrate pestsand animal parasites. The salts of the compounds of Formula 1 includeacid-addition salts with inorganic or organic acids such as hydrobromic,hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric,lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric,4-toluenesulfonic or valeric acids. Accordingly, the method of thepresent invention comprises compounds selected from Formula 1, N-oxidesand salts thereof.

By the procedures described in PCT Patent Publication WO 2005/085216together with methods known in the art, the following compounds ofTables 1-4 can be prepared. These tables disclose specific compoundsillustrative of compounds of Formula 1 useful in the present method. Thefollowing abbreviations are used in the Tables which follow: Me meansmethyl, Et means ethyl, n-Pr means CH₂CH₂CH₃, i-Pr means CH(CH₃)₂, c-Prmeans cyclopropyl, i-Bu means CH₂CH(CH₃)₂, s-Bu means CH(CH₃)CH₂CH₃,t-Bu means C(CH₃)₃, S(O) means sulfinyl, S(O)₂ means sulfonyl, and C(O)means carbonyl.

TABLE 1

R⁶ R¹ is Cl, R³ is Cl CH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMeCH₂CH₂CH₂SEt CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)MeCH₂CH₂CH₂S(O)Et CH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu)CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is Br, R³ is BrCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is CF₃, R³ is HCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is CF₃, R³ is FCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is CF₃, R³ is ClCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is CF₃, R³ is BrCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is CF₃, R³ is CF₃CH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is OCF₃, R³ is ClCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is OCH₂CF₃, R³ is FCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is OCH₂CF₃, R³ is ClCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is OCH₂CF₃, R³ is BrCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃

TABLE 2

R⁶ R¹ is Cl, R² is Cl, R³ is Cl CH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr)CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr)CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)Et CH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr)CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂Et CH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me)CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu)CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr)CH(Me)C(O)NH(i-Pr) CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu)CH₂(4-thiazolyl) CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃CH₂C(O)NH(c-Pr) CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂CH₂C(O)NHCH₂CF₃ CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃CH₂C(O)NHCH₂CH(Me)CF₃ CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr)CH(Me)C(O)NHCH₂CH₂Cl CH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃CH(Me)C(O)NHCH₂CH₂CF₃ CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹is Cl, R² is F, R³ is Cl CH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMeCH₂CH₂CH₂SEt CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)MeCH₂CH₂CH₂S(O)Et CH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu)CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is Cl, R² is CN, R³ isCl CH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEtCH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)MeCH₂CH₂CH₂S(O)Et CH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu)CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is Br, R² is H, R³ isH CH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEtCH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)MeCH₂CH₂CH₂S(O)Et CH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu)CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is Br, R² is H, R³ isCl CH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEtCH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)MeCH₂CH₂CH₂S(O)Et CH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu)CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is Br, R² is F, R³ isBr CH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEtCH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)MeCH₂CH₂CH₂S(O)Et CH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu)CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is Br, R² is Cl, R³ isCl CH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEtCH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)MeCH₂CH₂CH₂S(O)Et CH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu)CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is Br, R² is Cl, R³ isBr CH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEtCH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)MeCH₂CH₂CH₂S(O)Et CH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu)CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is OCF₃, R² is H, R³is Br CH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEtCH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)MeCH₂CH₂CH₂S(O)Et CH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu)CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃

TABLE 3

R⁶ R¹ is Cl, R³ is Cl CH₂CH₂OH CH₂CH₂OMe CH₂CH₂OEt CH₂CH₂O(i-Pr)CH₂CH(Me)OH CH₂CH(CF₃)OH CH₂C(Me)₂OH CH₂C(CF₃)(Me)OH CH(Me)CH₂OHC(Me)₂CH₂OH CH(Et)CH₂OH CH(i-Pr)CH₂OH CH(i-Bu)CH₂OH CH(Me)CH(CF₃)OHCH₂CH₂CH₂OH CH₂CH₂CH₂OMe CH₂CH₂CH₂OEt CH₂CH₂CH(CF₃)OH CH(Me)CH₂CH₂OHCH₂CH(Me)CH₂OH CH₂C(Me)₂CH₂OH CH₂CH₂CH(Me)OH CH₂CH₂C(Me)₂OH CH₂CH₂SMeCH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂S(i-Pr) CH₂CH₂S(i-Bu) CH₂CH(Me)SMeCH₂CH(CF₃)SMe CH₂C(Me)₂SMe CH(Me)CH₂SMe C(Me)₂CH₂SMe CH(Et)CH₂SMeCH(i-Pr)CH₂SMe CH(i-Bu)CH₂SMe CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂CH(Me)SMeCH₂CH₂CH(CF₃)SMe CH(Me)CH₂CH₂SMe CH(Et)CH₂CH₂SMe CH₂CH(Me)CH₂SMeCH₂C(Me)₂CH₂SMe CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr)CH₂CH₂S(O)(i-Pr) CH₂CH₂S(O)(i-Bu) CH₂CH(Me)S(O)Me CH₂CH(CF₃)S(O)MeCH₂C(Me)₂S(O)Me CH(Me)CH₂S(O)Me CH(Et)CH₂S(O)Me CH(i-Bu)CH₂S(O)MeCH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)Et CH₂CH₂CH₂S(O)(i-Bu) CH₂CH₂CH(Me)S(O)MeCH₂CH₂CH(CF₃)S(O)Me CH(Me)CH₂CH₂S(O)Me CH(Et)CH₂CH₂S(O)MeCH₂CH(Me)CH₂S(O)Me CH₂C(Me)₂CH₂S(O)Me CH₂(2-pyridinyl) CH₂CH₂SO₂MeCH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂SO₂(i-Pr) CH₂CH(Me)SO₂MeCH₂CH(CF₃)SO₂Me CH₂C(Me)₂SO₂Me CH(Me)CH₂SO₂Me C(Me)₂CH₂SO₂MeCH(Et)CH₂SO₂Me CH(i-Pr)CH₂SO₂Me CH(i-Bu)CH₂SO₂Me CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂CH₂CH(Me)SO₂Me CH₂CH₂CH(CF₃)SO₂Me CH(Me)CH₂CH₂SO₂MeCH(Et)CH₂CH₂SO₂Me CH₂CH(Me)CH₂SO₂Me CH₂C(Me)₂CH₂SO₂Me CH₂C(O)NHCH₂CH₂FCH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃ CH₂C(O)NHCH₂CH(Me)CH₂C(O)NHCH₂C(Me)₂F CH₂C(O)NH(CH₂)₂CH₂F CH₂C(O)NHCH₂CH₂CF₃CH₂C(O)NHCH₂CHFCF₃ CH₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NHCH(Me)CF₃CH₂C(O)NHCH(CF₃)₂ CH₂C(O)NHC(Me)₂CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH₂C(O)NH(CH₂)₂CF₂CF₃ CH₂C(O)NHCH₂(CF₂)₂CF₃ CH(Me)C(O)NHCH₂CH₂FCH(Me)C(O)NHCH₂CH₂Cl CH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃CH(Me)C(O)NHCH₂CH(Me)F CH(Me)C(O)NHCH₂C(Me)₂F CH(Me)C(O)NH(CH₂)₂CH₂FCH(Me)C(O)NHCH₂CH₂CF₃ CH(Me)C(O)NHCH₂CHFCF₃ CH(Me)C(O)NHCH₂CF₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH(CF₃)₂ CH(Me)C(O)NHC(Me)₂CF₃CH(Me)C(O)NHCH₂CH(Me)CF₃ CH(Me)C(O)NH(CH₂)₂CF₂CF₃CH(Me)C(O)NHCH₂(CF₂)₂CF₃ C(Me)₂C(O)NHCH₂CH₂F C(Me)₂C(O)NHCH₂CH₂ClC(Me)₂C(O)NHCH₂CHF₂ C(Me)₂C(O)NHCH₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)FC(Me)₂C(O)NHCH₂C(Me)₂F C(Me)₂C(O)NH(CH₂)₂CH₂F C(Me)₂C(O)NHCH₂CH₂CF₃C(Me)₂C(O)NHCH₂CHFCF₃ C(Me)₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂(4-thiazolyl) CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(n-Bu) CH₂C(O)NH(i-Bu)CH₂C(O)NH(s-Bu) CH₂C(O)NMe₂ CH₂C(O)NMe(Et) CH₂C(O)NEt₂ CH₂C(O)NMe(n-Pr)CH₂C(O)NMe(i-Pr) CH₂C(O)NMe(s-Bu) CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et)CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr) CH(Me)C(O)NH(n-Bu)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) C(Me)₂C(O)NH(Me) C(Me)₂C(O)NH(Et)C(Me)₂C(O)NH(n-Pr) C(Me)₂C(O)NH(i-Pr) (Me)₂C(O)NH(n-Bu)C(Me)₂C(O)NH(i-Bu) C(Me)₂C(O)NH(s-Bu) CH₂C(O)N(Me)CH₂CH₂FCH₂C(O)N(Me)CH₂CH₂Cl CH₂C(O)N(Me)CH₂CHF₂ CH₂C(O)N(Me)CH₂CF₃CH₂C(O)N(Me)CH₂CH₂CH₂F CH₂C(O)N(Me)CH₂CH₂CF₃ CH₂C(O)N(Me)CH₂CF₂CF₃CH₂C(O)N(Me)CH(Me)CF₃ CH₂C(O)N(Me)CH(CF₃)₂ CH₂C(O)N(Me)C(Me)₂CF₃CH(Me)C(O)N(Me)CH₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂Cl CH(Me)C(O)N(Me)CH₂CHF₂CH(Me)C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)(CH₂)₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂CF₃CH(Me)C(O)N(Me)CH₂CF₂CF₃ CH(Me)C(O)N(Me)CH(Me)CF₃CH(Me)C(O)N(Me)CH(CF₃)₂ CH(Me)C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)N(Me)CH₂CH₂FC(Me)₂C(O)N(Me)CH₂CH₂Cl C(Me)₂C(O)N(Me)CH₂CHF₂ C(Me)₂C(O)N(Me)CH₂CF₃C(Me)₂C(O)N(Me)CH₂CH₂CH₂F C(Me)₂C(O)N(Me)CH₂CH₂CF₃C(Me)₂C(O)N(Me)CH₂CF₂CF₃ C(Me)₂C(O)N(Me)CH(Me)CF₃C(Me)₂C(O)N(Me)CH(CF₃)₂ C(Me)₂C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)NHCH(Me)CF₃C(Me)₂C(O)NHCH(CF₃)₂ C(Me)₂C(O)NHC(Me)₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)CF₃C(Me)₂C(O)NH(CH₂)₂CF₂CF₃ C(Me)₂C(O)NHCH₂(CF₂)₂CF₃C(Me)₂C(O)NHCH(i-Pr)CF₃ CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) R¹ isBr, R³ is Br CH₂CH₂OH CH₂CH₂OMe CH₂CH₂OEt CH₂CH₂O(i-Pr) CH₂CH(Me)OHCH₂CH(CF₃)OH CH₂C(Me)₂OH CH₂C(CF₃)(Me)OH CH(Me)CH₂OH C(Me)₂CH₂OHCH(Et)CH₂OH CH(i-Pr)CH₂OH CH(i-Bu)CH₂OH CH(Me)CH(CF₃)OH CH₂CH₂CH₂OHCH₂CH₂CH₂OMe CH₂CH₂CH₂OEt CH₂CH₂CH(CF₃)OH CH(Me)CH₂CH₂OH CH₂CH(Me)CH₂OHCH₂C(Me)₂CH₂OH CH₂CH₂CH(Me)OH CH₂CH₂C(Me)₂OH CH₂CH₂SMe CH₂CH₂SEtCH₂CH₂S(n-Pr) CH₂CH₂S(i-Pr) CH₂CH₂S(i-Bu) CH₂CH(Me)SMe CH₂CH(CF₃)SMeCH₂C(Me)₂SMe CH(Me)CH₂SMe C(Me)₂CH₂SMe CH(Et)CH₂SMe CH(i-Pr)CH₂SMeCH(i-Bu)CH₂SMe CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂CH(Me)SMeCH₂CH₂CH(CF₃)SMe CH(Me)CH₂CH₂SMe CH(Et)CH₂CH₂SMe CH₂CH(Me)CH₂SMeCH₂C(Me)₂CH₂SMe CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr)CH₂CH₂S(O)(i-Pr) CH₂CH₂S(O)(i-Bu) CH₂CH(Me)S(O)Me CH₂CH(CF₃)S(O)MeCH₂C(Me)₂S(O)Me CH(Me)CH₂S(O)Me CH(Et)CH₂S(O)Me CH(i-Bu)CH₂S(O)MeCH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)Et CH₂CH₂CH₂S(O)(i-Bu) CH₂CH₂CH(Me)S(O)MeCH₂CH₂CH(CF₃)S(O)Me CH(Me)CH₂CH₂S(O)Me CH(Et)CH₂CH₂S(O)MeCH₂CH(Me)CH₂S(O)Me CH₂C(Me)₂CH₂S(O)Me CH₂(2-pyridinyl) CH₂CH₂SO₂MeCH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂SO₂(i-Pr) CH₂CH(Me)SO₂MeCH₂CH(CF₃)SO₂Me CH₂C(Me)₂SO₂Me CH(Me)CH₂SO₂Me C(Me)₂CH₂SO₂MeCH(Et)CH₂SO₂Me CH(i-Pr)CH₂SO₂Me CH(i-Bu)CH₂SO₂Me CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂CH₂CH(Me)SO₂Me CH₂CH₂CH(CF₃)SO₂Me CH(Me)CH₂CH₂SO₂MeCH(Et)CH₂CH₂SO₂Me CH₂CH(Me)CH₂SO₂Me CH₂C(Me)₂CH₂SO₂Me CH₂C(O)NHCH₂CH₂FCH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃ CH₂C(O)NHCH₂CH(Me)CH₂C(O)NHCH₂C(Me)₂F CH₂C(O)NH(CH₂)₂CH₂F CH₂C(O)NHCH₂CH₂CF₃CH₂C(O)NHCH₂CHFCF₃ CH₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NHCH(Me)CF₃CH₂C(O)NHCH(CF₃)₂ CH₂C(O)NHC(Me)₂CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH₂C(O)NH(CH₂)₂CF₂CF₃ CH₂C(O)NHCH₂(CF₂)₂CF₃ CH(Me)C(O)NHCH₂CH₂FCH(Me)C(O)NHCH₂CH₂Cl CH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃CH(Me)C(O)NHCH₂CH(Me)F CH(Me)C(O)NHCH₂C(Me)₂F CH(Me)C(O)NH(CH₂)₂CH₂FCH(Me)C(O)NHCH₂CH₂CF₃ CH(Me)C(O)NHCH₂CHFCF₃ CH(Me)C(O)NHCH₂CF₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH(CF₃)₂ CH(Me)C(O)NHC(Me)₂CF₃CH(Me)C(O)NHCH₂CH(Me)CF₃ CH(Me)C(O)NH(CH₂)₂CF₂CF₃CH(Me)C(O)NHCH₂(CF₂)₂CF₃ C(Me)₂C(O)NHCH₂CH₂F C(Me)₂C(O)NHCH₂CH₂ClC(Me)₂C(O)NHCH₂CHF₂ C(Me)₂C(O)NHCH₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)FC(Me)₂C(O)NHCH₂C(Me)₂F C(Me)₂C(O)NH(CH₂)₂CH₂F C(Me)₂C(O)NHCH₂CH₂CF₃C(Me)₂C(O)NHCH₂CHFCF₃ C(Me)₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂(4-thiazolyl) CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(n-Bu) CH₂C(O)NH(i-Bu)CH₂C(O)NH(s-Bu) CH₂C(O)NMe₂ CH₂C(O)NMe(Et) CH₂C(O)NEt₂ CH₂C(O)NMe(n-Pr)CH₂C(O)NMe(i-Pr) CH₂C(O)NMe(s-Bu) CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et)CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr) CH(Me)C(O)NH(n-Bu)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) C(Me)₂C(O)NH(Me) C(Me)₂C(O)NH(Et)C(Me)₂C(O)NH(n-Pr) C(Me)₂C(O)NH(i-Pr) (Me)₂C(O)NH(n-Bu)C(Me)₂C(O)NH(i-Bu) C(Me)₂C(O)NH(s-Bu) CH₂C(O)N(Me)CH₂CH₂FCH₂C(O)N(Me)CH₂CH₂Cl CH₂C(O)N(Me)CH₂CHF₂ CH₂C(O)N(Me)CH₂CF₃CH₂C(O)N(Me)CH₂CH₂CH₂F CH₂C(O)N(Me)CH₂CH₂CF₃ CH₂C(O)N(Me)CH₂CF₂CF₃CH₂C(O)N(Me)CH(Me)CF₃ CH₂C(O)N(Me)CH(CF₃)₂ CH₂C(O)N(Me)C(Me)₂CF₃CH(Me)C(O)N(Me)CH₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂Cl CH(Me)C(O)N(Me)CH₂CHF₂CH(Me)C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)(CH₂)₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂CF₃CH(Me)C(O)N(Me)CH₂CF₂CF₃ CH(Me)C(O)N(Me)CH(Me)CF₃CH(Me)C(O)N(Me)CH(CF₃)₂ CH(Me)C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)N(Me)CH₂CH₂FC(Me)₂C(O)N(Me)CH₂CH₂Cl C(Me)₂C(O)N(Me)CH₂CHF₂ C(Me)₂C(O)N(Me)CH₂CF₃C(Me)₂C(O)N(Me)CH₂CH₂CH₂F C(Me)₂C(O)N(Me)CH₂CH₂CF₃C(Me)₂C(O)N(Me)CH₂CF₂CF₃ C(Me)₂C(O)N(Me)CH(Me)CF₃C(Me)₂C(O)N(Me)CH(CF₃)₂ C(Me)₂C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)NHCH(Me)CF₃C(Me)₂C(O)NHCH(CF₃)₂ C(Me)₂C(O)NHC(Me)₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)CF₃C(Me)₂C(O)NH(CH₂)₂CF₂CF₃ C(Me)₂C(O)NHCH₂(CF₂)₂CF₃C(Me)₂C(O)NHCH(i-Pr)CF₃ CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) R¹ isCF₃, R³ is H CH₂CH₂OH CH₂CH₂OMe CH₂CH₂OEt CH₂CH₂O(i-Pr) CH₂CH(Me)OHCH₂CH(CF₃)OH CH₂C(Me)₂OH CH₂C(CF₃)(Me)OH CH(Me)CH₂OH C(Me)₂CH₂OHCH(Et)CH₂OH CH(i-Pr)CH₂OH CH(i-Bu)CH₂OH CH(Me)CH(CF₃)OH CH₂CH₂CH₂OHCH₂CH₂CH₂OMe CH₂CH₂CH₂OEt CH₂CH₂CH(CF₃)OH CH(Me)CH₂CH₂OH CH₂CH(Me)CH₂OHCH₂C(Me)₂CH₂OH CH₂CH₂CH(Me)OH CH₂CH₂C(Me)₂OH CH₂CH₂SMe CH₂CH₂SEtCH₂CH₂S(n-Pr) CH₂CH₂S(i-Pr) CH₂CH₂S(i-Bu) CH₂CH(Me)SMe CH₂CH(CF₃)SMeCH₂C(Me)₂SMe CH(Me)CH₂SMe C(Me)₂CH₂SMe CH(Et)CH₂SMe CH(i-Pr)CH₂SMeCH(i-Bu)CH₂SMe CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂CH(Me)SMeCH₂CH₂CH(CF₃)SMe CH(Me)CH₂CH₂SMe CH(Et)CH₂CH₂SMe CH₂CH(Me)CH₂SMeCH₂C(Me)₂CH₂SMe CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr)CH₂CH₂S(O)(i-Pr) CH₂CH₂S(O)(i-Bu) CH₂CH(Me)S(O)Me CH₂CH(CF₃)S(O)MeCH₂C(Me)₂S(O)Me CH(Me)CH₂S(O)Me CH(Et)CH₂S(O)Me CH(i-Bu)CH₂S(O)MeCH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)Et CH₂CH₂CH₂S(O)(i-Bu) CH₂CH₂CH(Me)S(O)MeCH₂CH₂CH(CF₃)S(O)Me CH(Me)CH₂CH₂S(O)Me CH(Et)CH₂CH₂S(O)MeCH₂CH(Me)CH₂S(O)Me CH₂C(Me)₂CH₂S(O)Me CH₂(2-pyridinyl) CH₂CH₂SO₂MeCH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂SO₂(i-Pr) CH₂CH(Me)SO₂MeCH₂CH(CF₃)SO₂Me CH₂C(Me)₂SO₂Me CH(Me)CH₂SO₂Me C(Me)₂CH₂SO₂MeCH(Et)CH₂SO₂Me CH(i-Pr)CH₂SO₂Me CH(i-Bu)CH₂SO₂Me CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂CH₂CH(Me)SO₂Me CH₂CH₂CH(CF₃)SO₂Me CH(Me)CH₂CH₂SO₂MeCH(Et)CH₂CH₂SO₂Me CH₂CH(Me)CH₂SO₂Me CH₂C(Me)₂CH₂SO₂Me CH₂C(O)NHCH₂CH₂FCH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃ CH₂C(O)NHCH₂CH(Me)CH₂C(O)NHCH₂C(Me)₂F CH₂C(O)NH(CH₂)₂CH₂F CH₂C(O)NHCH₂CH₂CF₃CH₂C(O)NHCH₂CHFCF₃ CH₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NHCH(Me)CF₃CH₂C(O)NHCH(CF₃)₂ CH₂C(O)NHC(Me)₂CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH₂C(O)NH(CH₂)₂CF₂CF₃ CH₂C(O)NHCH₂(CF₂)₂CF₃ CH(Me)C(O)NHCH₂CH₂FCH(Me)C(O)NHCH₂CH₂Cl CH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃CH(Me)C(O)NHCH₂CH(Me)F CH(Me)C(O)NHCH₂C(Me)₂F CH(Me)C(O)NH(CH₂)₂CH₂FCH(Me)C(O)NHCH₂CH₂CF₃ CH(Me)C(O)NHCH₂CHFCF₃ CH(Me)C(O)NHCH₂CF₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH(CF₃)₂ CH(Me)C(O)NHC(Me)₂CF₃CH(Me)C(O)NHCH₂CH(Me)CF₃ CH(Me)C(O)NH(CH₂)₂CF₂CF₃CH(Me)C(O)NHCH₂(CF₂)₂CF₃ C(Me)₂C(O)NHCH₂CH₂F C(Me)₂C(O)NHCH₂CH₂ClC(Me)₂C(O)NHCH₂CHF₂ C(Me)₂C(O)NHCH₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)FC(Me)₂C(O)NHCH₂C(Me)₂F C(Me)₂C(O)NH(CH₂)₂CH₂F C(Me)₂C(O)NHCH₂CH₂CF₃C(Me)₂C(O)NHCH₂CHFCF₃ C(Me)₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂(4-thiazolyl) CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(n-Bu) CH₂C(O)NH(i-Bu)CH₂C(O)NH(s-Bu) CH₂C(O)NMe₂ CH₂C(O)NMe(Et) CH₂C(O)NEt₂ CH₂C(O)NMe(n-Pr)CH₂C(O)NMe(i-Pr) CH₂C(O)NMe(s-Bu) CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et)CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr) CH(Me)C(O)NH(n-Bu)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) C(Me)₂C(O)NH(Me) C(Me)₂C(O)NH(Et)C(Me)₂C(O)NH(n-Pr) C(Me)₂C(O)NH(i-Pr) (Me)₂C(O)NH(n-Bu)C(Me)₂C(O)NH(i-Bu) C(Me)₂C(O)NH(s-Bu) CH₂C(O)N(Me)CH₂CH₂FCH₂C(O)N(Me)CH₂CH₂Cl CH₂C(O)N(Me)CH₂CHF₂ CH₂C(O)N(Me)CH₂CF₃CH₂C(O)N(Me)CH₂CH₂CH₂F CH₂C(O)N(Me)CH₂CH₂CF₃ CH₂C(O)N(Me)CH₂CF₂CF₃CH₂C(O)N(Me)CH(Me)CF₃ CH₂C(O)N(Me)CH(CF₃)₂ CH₂C(O)N(Me)C(Me)₂CF₃CH(Me)C(O)N(Me)CH₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂Cl CH(Me)C(O)N(Me)CH₂CHF₂CH(Me)C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)(CH₂)₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂CF₃CH(Me)C(O)N(Me)CH₂CF₂CF₃ CH(Me)C(O)N(Me)CH(Me)CF₃CH(Me)C(O)N(Me)CH(CF₃)₂ CH(Me)C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)N(Me)CH₂CH₂FC(Me)₂C(O)N(Me)CH₂CH₂Cl C(Me)₂C(O)N(Me)CH₂CHF₂ C(Me)₂C(O)N(Me)CH₂CF₃C(Me)₂C(O)N(Me)CH₂CH₂CH₂F C(Me)₂C(O)N(Me)CH₂CH₂CF₃C(Me)₂C(O)N(Me)CH₂CF₂CF₃ C(Me)₂C(O)N(Me)CH(Me)CF₃C(Me)₂C(O)N(Me)CH(CF₃)₂ C(Me)₂C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)NHCH(Me)CF₃C(Me)₂C(O)NHCH(CF₃)₂ C(Me)₂C(O)NHC(Me)₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)CF₃C(Me)₂C(O)NH(CH₂)₂CF₂CF₃ C(Me)₂C(O)NHCH₂(CF₂)₂CF₃C(Me)₂C(O)NHCH(i-Pr)CF₃ CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) R¹ isCF₃, R³ is F CH₂CH₂OH CH₂CH₂OMe CH₂CH₂OEt CH₂CH₂O(i-Pr) CH₂CH(Me)OHCH₂CH(CF₃)OH CH₂C(Me)₂OH CH₂C(CF₃)(Me)OH CH(Me)CH₂OH C(Me)₂CH₂OHCH(Et)CH₂OH CH(i-Pr)CH₂OH CH(i-Bu)CH₂OH CH(Me)CH(CF₃)OH CH₂CH₂CH₂OHCH₂CH₂CH₂OMe CH₂CH₂CH₂OEt CH₂CH₂CH(CF₃)OH CH(Me)CH₂CH₂OH CH₂CH(Me)CH₂OHCH₂C(Me)₂CH₂OH CH₂CH₂CH(Me)OH CH₂CH₂C(Me)₂OH CH₂CH₂SMe CH₂CH₂SEtCH₂CH₂S(n-Pr) CH₂CH₂S(i-Pr) CH₂CH₂S(i-Bu) CH₂CH(Me)SMe CH₂CH(CF₃)SMeCH₂C(Me)₂SMe CH(Me)CH₂SMe C(Me)₂CH₂SMe CH(Et)CH₂SMe CH(i-Pr)CH₂SMeCH(i-Bu)CH₂SMe CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂CH(Me)SMeCH₂CH₂CH(CF₃)SMe CH(Me)CH₂CH₂SMe CH(Et)CH₂CH₂SMe CH₂CH(Me)CH₂SMeCH₂C(Me)₂CH₂SMe CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr)CH₂CH₂S(O)(i-Pr) CH₂CH₂S(O)(i-Bu) CH₂CH(Me)S(O)Me CH₂CH(CF₃)S(O)MeCH₂C(Me)₂S(O)Me CH(Me)CH₂S(O)Me CH(Et)CH₂S(O)Me CH(i-Bu)CH₂S(O)MeCH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)Et CH₂CH₂CH₂S(O)(i-Bu) CH₂CH₂CH(Me)S(O)MeCH₂CH₂CH(CF₃)S(O)Me CH(Me)CH₂CH₂S(O)Me CH(Et)CH₂CH₂S(O)MeCH₂CH(Me)CH₂S(O)Me CH₂C(Me)₂CH₂S(O)Me CH₂(2-pyridinyl) CH₂CH₂SO₂MeCH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂SO₂(i-Pr) CH₂CH(Me)SO₂MeCH₂CH(CF₃)SO₂Me CH₂C(Me)₂SO₂Me CH(Me)CH₂SO₂Me C(Me)₂CH₂SO₂MeCH(Et)CH₂SO₂Me CH(i-Pr)CH₂SO₂Me CH(i-Bu)CH₂SO₂Me CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂CH₂CH(Me)SO₂Me CH₂CH₂CH(CF₃)SO₂Me CH(Me)CH₂CH₂SO₂MeCH(Et)CH₂CH₂SO₂Me CH₂CH(Me)CH₂SO₂Me CH₂C(Me)₂CH₂SO₂Me CH₂C(O)NHCH₂CH₂FCH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃ CH₂C(O)NHCH₂CH(Me)CH₂C(O)NHCH₂C(Me)₂F CH₂C(O)NH(CH₂)₂CH₂F CH₂C(O)NHCH₂CH₂CF₃CH₂C(O)NHCH₂CHFCF₃ CH₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NHCH(Me)CF₃CH₂C(O)NHCH(CF₃)₂ CH₂C(O)NHC(Me)₂CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH₂C(O)NH(CH₂)₂CF₂CF₃ CH₂C(O)NHCH₂(CF₂)₂CF₃ CH(Me)C(O)NHCH₂CH₂FCH(Me)C(O)NHCH₂CH₂Cl CH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃CH(Me)C(O)NHCH₂CH(Me)F CH(Me)C(O)NHCH₂C(Me)₂F CH(Me)C(O)NH(CH₂)₂CH₂FCH(Me)C(O)NHCH₂CH₂CF₃ CH(Me)C(O)NHCH₂CHFCF₃ CH(Me)C(O)NHCH₂CF₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH(CF₃)₂ CH(Me)C(O)NHC(Me)₂CF₃CH(Me)C(O)NHCH₂CH(Me)CF₃ CH(Me)C(O)NH(CH₂)₂CF₂CF₃CH(Me)C(O)NHCH₂(CF₂)₂CF₃ C(Me)₂C(O)NHCH₂CH₂F C(Me)₂C(O)NHCH₂CH₂ClC(Me)₂C(O)NHCH₂CHF₂ C(Me)₂C(O)NHCH₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)FC(Me)₂C(O)NHCH₂C(Me)₂F C(Me)₂C(O)NH(CH₂)₂CH₂F C(Me)₂C(O)NHCH₂CH₂CF₃C(Me)₂C(O)NHCH₂CHFCF₃ C(Me)₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂(4-thiazolyl) CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(n-Bu) CH₂C(O)NH(i-Bu)CH₂C(O)NH(s-Bu) CH₂C(O)NMe₂ CH₂C(O)NMe(Et) CH₂C(O)NEt₂ CH₂C(O)NMe(n-Pr)CH₂C(O)NMe(i-Pr) CH₂C(O)NMe(s-Bu) CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et)CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr) CH(Me)C(O)NH(n-Bu)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) C(Me)₂C(O)NH(Me) C(Me)₂C(O)NH(Et)C(Me)₂C(O)NH(n-Pr) C(Me)₂C(O)NH(i-Pr) (Me)₂C(O)NH(n-Bu)C(Me)₂C(O)NH(i-Bu) C(Me)₂C(O)NH(s-Bu) CH₂C(O)N(Me)CH₂CH₂FCH₂C(O)N(Me)CH₂CH₂Cl CH₂C(O)N(Me)CH₂CHF₂ CH₂C(O)N(Me)CH₂CF₃CH₂C(O)N(Me)CH₂CH₂CH₂F CH₂C(O)N(Me)CH₂CH₂CF₃ CH₂C(O)N(Me)CH₂CF₂CF₃CH₂C(O)N(Me)CH(Me)CF₃ CH₂C(O)N(Me)CH(CF₃)₂ CH₂C(O)N(Me)C(Me)₂CF₃CH(Me)C(O)N(Me)CH₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂Cl CH(Me)C(O)N(Me)CH₂CHF₂CH(Me)C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)(CH₂)₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂CF₃CH(Me)C(O)N(Me)CH₂CF₂CF₃ CH(Me)C(O)N(Me)CH(Me)CF₃CH(Me)C(O)N(Me)CH(CF₃)₂ CH(Me)C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)N(Me)CH₂CH₂FC(Me)₂C(O)N(Me)CH₂CH₂Cl C(Me)₂C(O)N(Me)CH₂CHF₂ C(Me)₂C(O)N(Me)CH₂CF₃C(Me)₂C(O)N(Me)CH₂CH₂CH₂F C(Me)₂C(O)N(Me)CH₂CH₂CF₃C(Me)₂C(O)N(Me)CH₂CF₂CF₃ C(Me)₂C(O)N(Me)CH(Me)CF₃C(Me)₂C(O)N(Me)CH(CF₃)₂ C(Me)₂C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)NHCH(Me)CF₃C(Me)₂C(O)NHCH(CF₃)₂ C(Me)₂C(O)NHC(Me)₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)CF₃C(Me)₂C(O)NH(CH₂)₂CF₂CF₃ C(Me)₂C(O)NHCH₂(CF₂)₂CF₃C(Me)₂C(O)NHCH(i-Pr)CF₃ CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) R¹ isCF₃, R³ is Cl CH₂CH₂OH CH₂CH₂OMe CH₂CH₂OEt CH₂CH₂O(i-Pr) CH₂CH(Me)OHCH₂CH(CF₃)OH CH₂C(Me)₂OH CH₂C(CF₃)(Me)OH CH(Me)CH₂OH C(Me)₂CH₂OHCH(Et)CH₂OH CH(i-Pr)CH₂OH CH(i-Bu)CH₂OH CH(Me)CH(CF₃)OH CH₂CH₂CH₂OHCH₂CH₂CH₂OMe CH₂CH₂CH₂OEt CH₂CH₂CH(CF₃)OH CH(Me)CH₂CH₂OH CH₂CH(Me)CH₂OHCH₂C(Me)₂CH₂OH CH₂CH₂CH(Me)OH CH₂CH₂C(Me)₂OH CH₂CH₂SMe CH₂CH₂SEtCH₂CH₂S(n-Pr) CH₂CH₂S(i-Pr) CH₂CH₂S(i-Bu) CH₂CH(Me)SMe CH₂CH(CF₃)SMeCH₂C(Me)₂SMe CH(Me)CH₂SMe C(Me)₂CH₂SMe CH(Et)CH₂SMe CH(i-Pr)CH₂SMeCH(i-Bu)CH₂SMe CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂CH(Me)SMeCH₂CH₂CH(CF₃)SMe CH(Me)CH₂CH₂SMe CH(Et)CH₂CH₂SMe CH₂CH(Me)CH₂SMeCH₂C(Me)₂CH₂SMe CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr)CH₂CH₂S(O)(i-Pr) CH₂CH₂S(O)(i-Bu) CH₂CH(Me)S(O)Me CH₂CH(CF₃)S(O)MeCH₂C(Me)₂S(O)Me CH(Me)CH₂S(O)Me CH(Et)CH₂S(O)Me CH(i-Bu)CH₂S(O)MeCH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)Et CH₂CH₂CH₂S(O)(i-Bu) CH₂CH₂CH(Me)S(O)MeCH₂CH₂CH(CF₃)S(O)Me CH(Me)CH₂CH₂S(O)Me CH(Et)CH₂CH₂S(O)MeCH₂CH(Me)CH₂S(O)Me CH₂C(Me)₂CH₂S(O)Me CH₂(2-pyridinyl) CH₂CH₂SO₂MeCH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂SO₂(i-Pr) CH₂CH(Me)SO₂MeCH₂CH(CF₃)SO₂Me CH₂C(Me)₂SO₂Me CH(Me)CH₂SO₂Me C(Me)₂CH₂SO₂MeCH(Et)CH₂SO₂Me CH(i-Pr)CH₂SO₂Me CH(i-Bu)CH₂SO₂Me CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂CH₂CH(Me)SO₂Me CH₂CH₂CH(CF₃)SO₂Me CH(Me)CH₂CH₂SO₂MeCH(Et)CH₂CH₂SO₂Me CH₂CH(Me)CH₂SO₂Me CH₂C(Me)₂CH₂SO₂Me CH₂C(O)NHCH₂CH₂FCH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃ CH₂C(O)NHCH₂CH(Me)CH₂C(O)NHCH₂C(Me)₂F CH₂C(O)NH(CH₂)₂CH₂F CH₂C(O)NHCH₂CH₂CF₃CH₂C(O)NHCH₂CHFCF₃ CH₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NHCH(Me)CF₃CH₂C(O)NHCH(CF₃)₂ CH₂C(O)NHC(Me)₂CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH₂C(O)NH(CH₂)₂CF₂CF₃ CH₂C(O)NHCH₂(CF₂)₂CF₃ CH(Me)C(O)NHCH₂CH₂FCH(Me)C(O)NHCH₂CH₂Cl CH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃CH(Me)C(O)NHCH₂CH(Me)F CH(Me)C(O)NHCH₂C(Me)₂F CH(Me)C(O)NH(CH₂)₂CH₂FCH(Me)C(O)NHCH₂CH₂CF₃ CH(Me)C(O)NHCH₂CHFCF₃ CH(Me)C(O)NHCH₂CF₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH(CF₃)₂ CH(Me)C(O)NHC(Me)₂CF₃CH(Me)C(O)NHCH₂CH(Me)CF₃ CH(Me)C(O)NH(CH₂)₂CF₂CF₃CH(Me)C(O)NHCH₂(CF₂)₂CF₃ C(Me)₂C(O)NHCH₂CH₂F C(Me)₂C(O)NHCH₂CH₂ClC(Me)₂C(O)NHCH₂CHF₂ C(Me)₂C(O)NHCH₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)FC(Me)₂C(O)NHCH₂C(Me)₂F C(Me)₂C(O)NH(CH₂)₂CH₂F C(Me)₂C(O)NHCH₂CH₂CF₃C(Me)₂C(O)NHCH₂CHFCF₃ C(Me)₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂(4-thiazolyl) CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(n-Bu) CH₂C(O)NH(i-Bu)CH₂C(O)NH(s-Bu) CH₂C(O)NMe₂ CH₂C(O)NMe(Et) CH₂C(O)NEt₂ CH₂C(O)NMe(n-Pr)CH₂C(O)NMe(i-Pr) CH₂C(O)NMe(s-Bu) CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et)CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr) CH(Me)C(O)NH(n-Bu)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) C(Me)₂C(O)NH(Me) C(Me)₂C(O)NH(Et)C(Me)₂C(O)NH(n-Pr) C(Me)₂C(O)NH(i-Pr) (Me)₂C(O)NH(n-Bu)C(Me)₂C(O)NH(i-Bu) C(Me)₂C(O)NH(s-Bu) CH₂C(O)N(Me)CH₂CH₂FCH₂C(O)N(Me)CH₂CH₂Cl CH₂C(O)N(Me)CH₂CHF₂ CH₂C(O)N(Me)CH₂CF₃CH₂C(O)N(Me)CH₂CH₂CH₂F CH₂C(O)N(Me)CH₂CH₂CF₃ CH₂C(O)N(Me)CH₂CF₂CF₃CH₂C(O)N(Me)CH(Me)CF₃ CH₂C(O)N(Me)CH(CF₃)₂ CH₂C(O)N(Me)C(Me)₂CF₃CH(Me)C(O)N(Me)CH₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂Cl CH(Me)C(O)N(Me)CH₂CHF₂CH(Me)C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)(CH₂)₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂CF₃CH(Me)C(O)N(Me)CH₂CF₂CF₃ CH(Me)C(O)N(Me)CH(Me)CF₃CH(Me)C(O)N(Me)CH(CF₃)₂ CH(Me)C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)N(Me)CH₂CH₂FC(Me)₂C(O)N(Me)CH₂CH₂Cl C(Me)₂C(O)N(Me)CH₂CHF₂ C(Me)₂C(O)N(Me)CH₂CF₃C(Me)₂C(O)N(Me)CH₂CH₂CH₂F C(Me)₂C(O)N(Me)CH₂CH₂CF₃C(Me)₂C(O)N(Me)CH₂CF₂CF₃ C(Me)₂C(O)N(Me)CH(Me)CF₃C(Me)₂C(O)N(Me)CH(CF₃)₂ C(Me)₂C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)NHCH(Me)CF₃C(Me)₂C(O)NHCH(CF₃)₂ C(Me)₂C(O)NHC(Me)₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)CF₃C(Me)₂C(O)NH(CH₂)₂CF₂CF₃ C(Me)₂C(O)NHCH₂(CF₂)₂CF₃C(Me)₂C(O)NHCH(i-Pr)CF₃ CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) R¹ isCF₃, R³ is Br CH₂CH₂OH CH₂CH₂OMe CH₂CH₂OEt CH₂CH₂O(i-Pr) CH₂CH(Me)OHCH₂CH(CF₃)OH CH₂C(Me)₂OH CH₂C(CF₃)(Me)OH CH(Me)CH₂OH C(Me)₂CH₂OHCH(Et)CH₂OH CH(i-Pr)CH₂OH CH(i-Bu)CH₂OH CH(Me)CH(CF₃)OH CH₂CH₂CH₂OHCH₂CH₂CH₂OMe CH₂CH₂CH₂OEt CH₂CH₂CH(CF₃)OH CH(Me)CH₂CH₂OH CH₂CH(Me)CH₂OHCH₂C(Me)₂CH₂OH CH₂CH₂CH(Me)OH CH₂CH₂C(Me)₂OH CH₂CH₂SMe CH₂CH₂SEtCH₂CH₂S(n-Pr) CH₂CH₂S(i-Pr) CH₂CH₂S(i-Bu) CH₂CH(Me)SMe CH₂CH(CF₃)SMeCH₂C(Me)₂SMe CH(Me)CH₂SMe C(Me)₂CH₂SMe CH(Et)CH₂SMe CH(i-Pr)CH₂SMeCH(i-Bu)CH₂SMe CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂CH(Me)SMeCH₂CH₂CH(CF₃)SMe CH(Me)CH₂CH₂SMe CH(Et)CH₂CH₂SMe CH₂CH(Me)CH₂SMeCH₂C(Me)₂CH₂SMe CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr)CH₂CH₂S(O)(i-Pr) CH₂CH₂S(O)(i-Bu) CH₂CH(Me)S(O)Me CH₂CH(CF₃)S(O)MeCH₂C(Me)₂S(O)Me CH(Me)CH₂S(O)Me CH(Et)CH₂S(O)Me CH(i-Bu)CH₂S(O)MeCH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)Et CH₂CH₂CH₂S(O)(i-Bu) CH₂CH₂CH(Me)S(O)MeCH₂CH₂CH(CF₃)S(O)Me CH(Me)CH₂CH₂S(O)Me CH(Et)CH₂CH₂S(O)MeCH₂CH(Me)CH₂S(O)Me CH₂C(Me)₂CH₂S(O)Me CH₂(2-pyridinyl) CH₂CH₂SO₂MeCH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂SO₂(i-Pr) CH₂CH(Me)SO₂MeCH₂CH(CF₃)SO₂Me CH₂C(Me)₂SO₂Me CH(Me)CH₂SO₂Me C(Me)₂CH₂SO₂MeCH(Et)CH₂SO₂Me CH(i-Pr)CH₂SO₂Me CH(i-Bu)CH₂SO₂Me CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂CH₂CH(Me)SO₂Me CH₂CH₂CH(CF₃)SO₂Me CH(Me)CH₂CH₂SO₂MeCH(Et)CH₂CH₂SO₂Me CH₂CH(Me)CH₂SO₂Me CH₂C(Me)₂CH₂SO₂Me CH₂C(O)NHCH₂CH₂FCH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃ CH₂C(O)NHCH₂CH(Me)CH₂C(O)NHCH₂C(Me)₂F CH₂C(O)NH(CH₂)₂CH₂F CH₂C(O)NHCH₂CH₂CF₃CH₂C(O)NHCH₂CHFCF₃ CH₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NHCH(Me)CF₃CH₂C(O)NHCH(CF₃)₂ CH₂C(O)NHC(Me)₂CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH₂C(O)NH(CH₂)₂CF₂CF₃ CH₂C(O)NHCH₂(CF₂)₂CF₃ CH(Me)C(O)NHCH₂CH₂FCH(Me)C(O)NHCH₂CH₂Cl CH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃CH(Me)C(O)NHCH₂CH(Me)F CH(Me)C(O)NHCH₂C(Me)₂F CH(Me)C(O)NH(CH₂)₂CH₂FCH(Me)C(O)NHCH₂CH₂CF₃ CH(Me)C(O)NHCH₂CHFCF₃ CH(Me)C(O)NHCH₂CF₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH(CF₃)₂ CH(Me)C(O)NHC(Me)₂CF₃CH(Me)C(O)NHCH₂CH(Me)CF₃ CH(Me)C(O)NH(CH₂)₂CF₂CF₃CH(Me)C(O)NHCH₂(CF₂)₂CF₃ C(Me)₂C(O)NHCH₂CH₂F C(Me)₂C(O)NHCH₂CH₂ClC(Me)₂C(O)NHCH₂CHF₂ C(Me)₂C(O)NHCH₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)FC(Me)₂C(O)NHCH₂C(Me)₂F C(Me)₂C(O)NH(CH₂)₂CH₂F C(Me)₂C(O)NHCH₂CH₂CF₃C(Me)₂C(O)NHCH₂CHFCF₃ C(Me)₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂(4-thiazolyl) CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(n-Bu) CH₂C(O)NH(i-Bu)CH₂C(O)NH(s-Bu) CH₂C(O)NMe₂ CH₂C(O)NMe(Et) CH₂C(O)NEt₂ CH₂C(O)NMe(n-Pr)CH₂C(O)NMe(i-Pr) CH₂C(O)NMe(s-Bu) CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et)CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr) CH(Me)C(O)NH(n-Bu)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) C(Me)₂C(O)NH(Me) C(Me)₂C(O)NH(Et)C(Me)₂C(O)NH(n-Pr) C(Me)₂C(O)NH(i-Pr) (Me)₂C(O)NH(n-Bu)C(Me)₂C(O)NH(i-Bu) C(Me)₂C(O)NH(s-Bu) CH₂C(O)N(Me)CH₂CH₂FCH₂C(O)N(Me)CH₂CH₂Cl CH₂C(O)N(Me)CH₂CHF₂ CH₂C(O)N(Me)CH₂CF₃CH₂C(O)N(Me)CH₂CH₂CH₂F CH₂C(O)N(Me)CH₂CH₂CF₃ CH₂C(O)N(Me)CH₂CF₂CF₃CH₂C(O)N(Me)CH(Me)CF₃ CH₂C(O)N(Me)CH(CF₃)₂ CH₂C(O)N(Me)C(Me)₂CF₃CH(Me)C(O)N(Me)CH₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂Cl CH(Me)C(O)N(Me)CH₂CHF₂CH(Me)C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)(CH₂)₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂CF₃CH(Me)C(O)N(Me)CH₂CF₂CF₃ CH(Me)C(O)N(Me)CH(Me)CF₃CH(Me)C(O)N(Me)CH(CF₃)₂ CH(Me)C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)N(Me)CH₂CH₂FC(Me)₂C(O)N(Me)CH₂CH₂Cl C(Me)₂C(O)N(Me)CH₂CHF₂ C(Me)₂C(O)N(Me)CH₂CF₃C(Me)₂C(O)N(Me)CH₂CH₂CH₂F C(Me)₂C(O)N(Me)CH₂CH₂CF₃C(Me)₂C(O)N(Me)CH₂CF₂CF₃ C(Me)₂C(O)N(Me)CH(Me)CF₃C(Me)₂C(O)N(Me)CH(CF₃)₂ C(Me)₂C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)NHCH(Me)CF₃C(Me)₂C(O)NHCH(CF₃)₂ C(Me)₂C(O)NHC(Me)₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)CF₃C(Me)₂C(O)NH(CH₂)₂CF₂CF₃ C(Me)₂C(O)NHCH₂(CF₂)₂CF₃C(Me)₂C(O)NHCH(i-Pr)CF₃ CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) R¹ isCF₃, R³ is CF₃ CH₂CH₂OH CH₂CH₂OMe CH₂CH₂OEt CH₂CH₂O(i-Pr) CH₂CH(Me)OHCH₂CH(CF₃)OH CH₂C(Me)₂OH CH₂C(CF₃)(Me)OH CH(Me)CH₂OH C(Me)₂CH₂OHCH(Et)CH₂OH CH(i-Pr)CH₂OH CH(i-Bu)CH₂OH CH(Me)CH(CF₃)OH CH₂CH₂CH₂OHCH₂CH₂CH₂OMe CH₂CH₂CH₂OEt CH₂CH₂CH(CF₃)OH CH(Me)CH₂CH₂OH CH₂CH(Me)CH₂OHCH₂C(Me)₂CH₂OH CH₂CH₂CH(Me)OH CH₂CH₂C(Me)₂OH CH₂CH₂SMe CH₂CH₂SEtCH₂CH₂S(n-Pr) CH₂CH₂S(i-Pr) CH₂CH₂S(i-Bu) CH₂CH(Me)SMe CH₂CH(CF₃)SMeCH₂C(Me)₂SMe CH(Me)CH₂SMe C(Me)₂CH₂SMe CH(Et)CH₂SMe CH(i-Pr)CH₂SMeCH(i-Bu)CH₂SMe CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂CH(Me)SMeCH₂CH₂CH(CF₃)SMe CH(Me)CH₂CH₂SMe CH(Et)CH₂CH₂SMe CH₂CH(Me)CH₂SMeCH₂C(Me)₂CH₂SMe CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr)CH₂CH₂S(O)(i-Pr) CH₂CH₂S(O)(i-Bu) CH₂CH(Me)S(O)Me CH₂CH(CF₃)S(O)MeCH₂C(Me)₂S(O)Me CH(Me)CH₂S(O)Me CH(Et)CH₂S(O)Me CH(i-Bu)CH₂S(O)MeCH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)Et CH₂CH₂CH₂S(O)(i-Bu) CH₂CH₂CH(Me)S(O)MeCH₂CH₂CH(CF₃)S(O)Me CH(Me)CH₂CH₂S(O)Me CH(Et)CH₂CH₂S(O)MeCH₂CH(Me)CH₂S(O)Me CH₂C(Me)₂CH₂S(O)Me CH₂(2-pyridinyl) CH₂CH₂SO₂MeCH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂SO₂(i-Pr) CH₂CH(Me)SO₂MeCH₂CH(CF₃)SO₂Me CH₂C(Me)₂SO₂Me CH(Me)CH₂SO₂Me C(Me)₂CH₂SO₂MeCH(Et)CH₂SO₂Me CH(i-Pr)CH₂SO₂Me CH(i-Bu)CH₂SO₂Me CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂CH₂CH(Me)SO₂Me CH₂CH₂CH(CF₃)SO₂Me CH(Me)CH₂CH₂SO₂MeCH(Et)CH₂CH₂SO₂Me CH₂CH(Me)CH₂SO₂Me CH₂C(Me)₂CH₂SO₂Me CH₂C(O)NHCH₂CH₂FCH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃ CH₂C(O)NHCH₂CH(Me)CH₂C(O)NHCH₂C(Me)₂F CH₂C(O)NH(CH₂)₂CH₂F CH₂C(O)NHCH₂CH₂CF₃CH₂C(O)NHCH₂CHFCF₃ CH₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NHCH(Me)CF₃CH₂C(O)NHCH(CF₃)₂ CH₂C(O)NHC(Me)₂CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH₂C(O)NH(CH₂)₂CF₂CF₃ CH₂C(O)NHCH₂(CF₂)₂CF₃ CH(Me)C(O)NHCH₂CH₂FCH(Me)C(O)NHCH₂CH₂Cl CH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃CH(Me)C(O)NHCH₂CH(Me)F CH(Me)C(O)NHCH₂C(Me)₂F CH(Me)C(O)NH(CH₂)₂CH₂FCH(Me)C(O)NHCH₂CH₂CF₃ CH(Me)C(O)NHCH₂CHFCF₃ CH(Me)C(O)NHCH₂CF₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH(CF₃)₂ CH(Me)C(O)NHC(Me)₂CF₃CH(Me)C(O)NHCH₂CH(Me)CF₃ CH(Me)C(O)NH(CH₂)₂CF₂CF₃CH(Me)C(O)NHCH₂(CF₂)₂CF₃ C(Me)₂C(O)NHCH₂CH₂F C(Me)₂C(O)NHCH₂CH₂ClC(Me)₂C(O)NHCH₂CHF₂ C(Me)₂C(O)NHCH₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)FC(Me)₂C(O)NHCH₂C(Me)₂F C(Me)₂C(O)NH(CH₂)₂CH₂F C(Me)₂C(O)NHCH₂CH₂CF₃C(Me)₂C(O)NHCH₂CHFCF₃ C(Me)₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂(4-thiazolyl) CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(n-Bu) CH₂C(O)NH(i-Bu)CH₂C(O)NH(s-Bu) CH₂C(O)NMe₂ CH₂C(O)NMe(Et) CH₂C(O)NEt₂ CH₂C(O)NMe(n-Pr)CH₂C(O)NMe(i-Pr) CH₂C(O)NMe(s-Bu) CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et)CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr) CH(Me)C(O)NH(n-Bu)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) C(Me)₂C(O)NH(Me) C(Me)₂C(O)NH(Et)C(Me)₂C(O)NH(n-Pr) C(Me)₂C(O)NH(i-Pr) (Me)₂C(O)NH(n-Bu)C(Me)₂C(O)NH(i-Bu) C(Me)₂C(O)NH(s-Bu) CH₂C(O)N(Me)CH₂CH₂FCH₂C(O)N(Me)CH₂CH₂Cl CH₂C(O)N(Me)CH₂CHF₂ CH₂C(O)N(Me)CH₂CF₃CH₂C(O)N(Me)CH₂CH₂CH₂F CH₂C(O)N(Me)CH₂CH₂CF₃ CH₂C(O)N(Me)CH₂CF₂CF₃CH₂C(O)N(Me)CH(Me)CF₃ CH₂C(O)N(Me)CH(CF₃)₂ CH₂C(O)N(Me)C(Me)₂CF₃CH(Me)C(O)N(Me)CH₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂Cl CH(Me)C(O)N(Me)CH₂CHF₂CH(Me)C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)(CH₂)₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂CF₃CH(Me)C(O)N(Me)CH₂CF₂CF₃ CH(Me)C(O)N(Me)CH(Me)CF₃CH(Me)C(O)N(Me)CH(CF₃)₂ CH(Me)C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)N(Me)CH₂CH₂FC(Me)₂C(O)N(Me)CH₂CH₂Cl C(Me)₂C(O)N(Me)CH₂CHF₂ C(Me)₂C(O)N(Me)CH₂CF₃C(Me)₂C(O)N(Me)CH₂CH₂CH₂F C(Me)₂C(O)N(Me)CH₂CH₂CF₃C(Me)₂C(O)N(Me)CH₂CF₂CF₃ C(Me)₂C(O)N(Me)CH(Me)CF₃C(Me)₂C(O)N(Me)CH(CF₃)₂ C(Me)₂C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)NHCH(Me)CF₃C(Me)₂C(O)NHCH(CF₃)₂ C(Me)₂C(O)NHC(Me)₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)CF₃C(Me)₂C(O)NH(CH₂)₂CF₂CF₃ C(Me)₂C(O)NHCH₂(CF₂)₂CF₃C(Me)₂C(O)NHCH(i-Pr)CF₃ CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) R¹ isOCF₃, R³ is Cl CH₂CH₂OH CH₂CH₂OMe CH₂CH₂OEt CH₂CH₂O(i-Pr) CH₂CH(Me)OHCH₂CH(CF₃)OH CH₂C(Me)₂OH CH₂C(CF₃)(Me)OH CH(Me)CH₂OH C(Me)₂CH₂OHCH(Et)CH₂OH CH(i-Pr)CH₂OH CH(i-Bu)CH₂OH CH(Me)CH(CF₃)OH CH₂CH₂CH₂OHCH₂CH₂CH₂OMe CH₂CH₂CH₂OEt CH₂CH₂CH(CF₃)OH CH(Me)CH₂CH₂OH CH₂CH(Me)CH₂OHCH₂C(Me)₂CH₂OH CH₂CH₂CH(Me)OH CH₂CH₂C(Me)₂OH CH₂CH₂SMe CH₂CH₂SEtCH₂CH₂S(n-Pr) CH₂CH₂S(i-Pr) CH₂CH₂S(i-Bu) CH₂CH(Me)SMe CH₂CH(CF₃)SMeCH₂C(Me)₂SMe CH(Me)CH₂SMe C(Me)₂CH₂SMe CH(Et)CH₂SMe CH(i-Pr)CH₂SMeCH(i-Bu)CH₂SMe CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂CH(Me)SMeCH₂CH₂CH(CF₃)SMe CH(Me)CH₂CH₂SMe CH(Et)CH₂CH₂SMe CH₂CH(Me)CH₂SMeCH₂C(Me)₂CH₂SMe CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr)CH₂CH₂S(O)(i-Pr) CH₂CH₂S(O)(i-Bu) CH₂CH(Me)S(O)Me CH₂CH(CF₃)S(O)MeCH₂C(Me)₂S(O)Me CH(Me)CH₂S(O)Me CH(Et)CH₂S(O)Me CH(i-Bu)CH₂S(O)MeCH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)Et CH₂CH₂CH₂S(O)(i-Bu) CH₂CH₂CH(Me)S(O)MeCH₂CH₂CH(CF₃)S(O)Me CH(Me)CH₂CH₂S(O)Me CH(Et)CH₂CH₂S(O)MeCH₂CH(Me)CH₂S(O)Me CH₂C(Me)₂CH₂S(O)Me CH₂(2-pyridinyl) CH₂CH₂SO₂MeCH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂SO₂(i-Pr) CH₂CH(Me)SO₂MeCH₂CH(CF₃)SO₂Me CH₂C(Me)₂SO₂Me CH(Me)CH₂SO₂Me C(Me)₂CH₂SO₂MeCH(Et)CH₂SO₂Me CH(i-Pr)CH₂SO₂Me CH(i-Bu)CH₂SO₂Me CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂CH₂CH(Me)SO₂Me CH₂CH₂CH(CF₃)SO₂Me CH(Me)CH₂CH₂SO₂MeCH(Et)CH₂CH₂SO₂Me CH₂CH(Me)CH₂SO₂Me CH₂C(Me)₂CH₂SO₂Me CH₂C(O)NHCH₂CH₂FCH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃ CH₂C(O)NHCH₂CH(Me)CH₂C(O)NHCH₂C(Me)₂F CH₂C(O)NH(CH₂)₂CH₂F CH₂C(O)NHCH₂CH₂CF₃CH₂C(O)NHCH₂CHFCF₃ CH₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NHCH(Me)CF₃CH₂C(O)NHCH(CF₃)₂ CH₂C(O)NHC(Me)₂CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH₂C(O)NH(CH₂)₂CF₂CF₃ CH₂C(O)NHCH₂(CF₂)₂CF₃ CH(Me)C(O)NHCH₂CH₂FCH(Me)C(O)NHCH₂CH₂Cl CH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃CH(Me)C(O)NHCH₂CH(Me)F CH(Me)C(O)NHCH₂C(Me)₂F CH(Me)C(O)NH(CH₂)₂CH₂FCH(Me)C(O)NHCH₂CH₂CF₃ CH(Me)C(O)NHCH₂CHFCF₃ CH(Me)C(O)NHCH₂CF₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH(CF₃)₂ CH(Me)C(O)NHC(Me)₂CF₃CH(Me)C(O)NHCH₂CH(Me)CF₃ CH(Me)C(O)NH(CH₂)₂CF₂CF₃CH(Me)C(O)NHCH₂(CF₂)₂CF₃ C(Me)₂C(O)NHCH₂CH₂F C(Me)₂C(O)NHCH₂CH₂ClC(Me)₂C(O)NHCH₂CHF₂ C(Me)₂C(O)NHCH₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)FC(Me)₂C(O)NHCH₂C(Me)₂F C(Me)₂C(O)NH(CH₂)₂CH₂F C(Me)₂C(O)NHCH₂CH₂CF₃C(Me)₂C(O)NHCH₂CHFCF₃ C(Me)₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂(4-thiazolyl) CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(n-Bu) CH₂C(O)NH(i-Bu)CH₂C(O)NH(s-Bu) CH₂C(O)NMe₂ CH₂C(O)NMe(Et) CH₂C(O)NEt₂ CH₂C(O)NMe(n-Pr)CH₂C(O)NMe(i-Pr) CH₂C(O)NMe(s-Bu) CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et)CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr) CH(Me)C(O)NH(n-Bu)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) C(Me)₂C(O)NH(Me) C(Me)₂C(O)NH(Et)C(Me)₂C(O)NH(n-Pr) C(Me)₂C(O)NH(i-Pr) (Me)₂C(O)NH(n-Bu)C(Me)₂C(O)NH(i-Bu) C(Me)₂C(O)NH(s-Bu) CH₂C(O)N(Me)CH₂CH₂FCH₂C(O)N(Me)CH₂CH₂Cl CH₂C(O)N(Me)CH₂CHF₂ CH₂C(O)N(Me)CH₂CF₃CH₂C(O)N(Me)CH₂CH₂CH₂F CH₂C(O)N(Me)CH₂CH₂CF₃ CH₂C(O)N(Me)CH₂CF₂CF₃CH₂C(O)N(Me)CH(Me)CF₃ CH₂C(O)N(Me)CH(CF₃)₂ CH₂C(O)N(Me)C(Me)₂CF₃CH(Me)C(O)N(Me)CH₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂Cl CH(Me)C(O)N(Me)CH₂CHF₂CH(Me)C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)(CH₂)₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂CF₃CH(Me)C(O)N(Me)CH₂CF₂CF₃ CH(Me)C(O)N(Me)CH(Me)CF₃CH(Me)C(O)N(Me)CH(CF₃)₂ CH(Me)C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)N(Me)CH₂CH₂FC(Me)₂C(O)N(Me)CH₂CH₂Cl C(Me)₂C(O)N(Me)CH₂CHF₂ C(Me)₂C(O)N(Me)CH₂CF₃C(Me)₂C(O)N(Me)CH₂CH₂CH₂F C(Me)₂C(O)N(Me)CH₂CH₂CF₃C(Me)₂C(O)N(Me)CH₂CF₂CF₃ C(Me)₂C(O)N(Me)CH(Me)CF₃C(Me)₂C(O)N(Me)CH(CF₃)₂ C(Me)₂C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)NHCH(Me)CF₃C(Me)₂C(O)NHCH(CF₃)₂ C(Me)₂C(O)NHC(Me)₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)CF₃C(Me)₂C(O)NH(CH₂)₂CF₂CF₃ C(Me)₂C(O)NHCH₂(CF₂)₂CF₃C(Me)₂C(O)NHCH(i-Pr)CF₃ CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) R¹ isOCH₂CF₃, R³ is F CH₂CH₂OH CH₂CH₂OMe CH₂CH₂OEt CH₂CH₂O(i-Pr) CH₂CH(Me)OHCH₂CH(CF₃)OH CH₂C(Me)₂OH CH₂C(CF₃)(Me)OH CH(Me)CH₂OH C(Me)₂CH₂OHCH(Et)CH₂OH CH(i-Pr)CH₂OH CH(i-Bu)CH₂OH CH(Me)CH(CF₃)OH CH₂CH₂CH₂OHCH₂CH₂CH₂OMe CH₂CH₂CH₂OEt CH₂CH₂CH(CF₃)OH CH(Me)CH₂CH₂OH CH₂CH(Me)CH₂OHCH₂C(Me)₂CH₂OH CH₂CH₂CH(Me)OH CH₂CH₂C(Me)₂OH CH₂CH₂SMe CH₂CH₂SEtCH₂CH₂S(n-Pr) CH₂CH₂S(i-Pr) CH₂CH₂S(i-Bu) CH₂CH(Me)SMe CH₂CH(CF₃)SMeCH₂C(Me)₂SMe CH(Me)CH₂SMe C(Me)₂CH₂SMe CH(Et)CH₂SMe CH(i-Pr)CH₂SMeCH(i-Bu)CH₂SMe CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂CH(Me)SMeCH₂CH₂CH(CF₃)SMe CH(Me)CH₂CH₂SMe CH(Et)CH₂CH₂SMe CH₂CH(Me)CH₂SMeCH₂C(Me)₂CH₂SMe CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr)CH₂CH₂S(O)(i-Pr) CH₂CH₂S(O)(i-Bu) CH₂CH(Me)S(O)Me CH₂CH(CF₃)S(O)MeCH₂C(Me)₂S(O)Me CH(Me)CH₂S(O)Me CH(Et)CH₂S(O)Me CH(i-Bu)CH₂S(O)MeCH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)Et CH₂CH₂CH₂S(O)(i-Bu) CH₂CH₂CH(Me)S(O)MeCH₂CH₂CH(CF₃)S(O)Me CH(Me)CH₂CH₂S(O)Me CH(Et)CH₂CH₂S(O)MeCH₂CH(Me)CH₂S(O)Me CH₂C(Me)₂CH₂S(O)Me CH₂(2-pyridinyl) CH₂CH₂SO₂MeCH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂SO₂(i-Pr) CH₂CH(Me)SO₂MeCH₂CH(CF₃)SO₂Me CH₂C(Me)₂SO₂Me CH(Me)CH₂SO₂Me C(Me)₂CH₂SO₂MeCH(Et)CH₂SO₂Me CH(i-Pr)CH₂SO₂Me CH(i-Bu)CH₂SO₂Me CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂CH₂CH(Me)SO₂Me CH₂CH₂CH(CF₃)SO₂Me CH(Me)CH₂CH₂SO₂MeCH(Et)CH₂CH₂SO₂Me CH₂CH(Me)CH₂SO₂Me CH₂C(Me)₂CH₂SO₂Me CH₂C(O)NHCH₂CH₂FCH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃ CH₂C(O)NHCH₂CH(Me)CH₂C(O)NHCH₂C(Me)₂F CH₂C(O)NH(CH₂)₂CH₂F CH₂C(O)NHCH₂CH₂CF₃CH₂C(O)NHCH₂CHFCF₃ CH₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NHCH(Me)CF₃CH₂C(O)NHCH(CF₃)₂ CH₂C(O)NHC(Me)₂CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH₂C(O)NH(CH₂)₂CF₂CF₃ CH₂C(O)NHCH₂(CF₂)₂CF₃ CH(Me)C(O)NHCH₂CH₂FCH(Me)C(O)NHCH₂CH₂Cl CH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃CH(Me)C(O)NHCH₂CH(Me)F CH(Me)C(O)NHCH₂C(Me)₂F CH(Me)C(O)NH(CH₂)₂CH₂FCH(Me)C(O)NHCH₂CH₂CF₃ CH(Me)C(O)NHCH₂CHFCF₃ CH(Me)C(O)NHCH₂CF₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH(CF₃)₂ CH(Me)C(O)NHC(Me)₂CF₃CH(Me)C(O)NHCH₂CH(Me)CF₃ CH(Me)C(O)NH(CH₂)₂CF₂CF₃CH(Me)C(O)NHCH₂(CF₂)₂CF₃ C(Me)₂C(O)NHCH₂CH₂F C(Me)₂C(O)NHCH₂CH₂ClC(Me)₂C(O)NHCH₂CHF₂ C(Me)₂C(O)NHCH₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)FC(Me)₂C(O)NHCH₂C(Me)₂F C(Me)₂C(O)NH(CH₂)₂CH₂F C(Me)₂C(O)NHCH₂CH₂CF₃C(Me)₂C(O)NHCH₂CHFCF₃ C(Me)₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂(4-thiazolyl) CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(n-Bu) CH₂C(O)NH(i-Bu)CH₂C(O)NH(s-Bu) CH₂C(O)NMe₂ CH₂C(O)NMe(Et) CH₂C(O)NEt₂ CH₂C(O)NMe(n-Pr)CH₂C(O)NMe(i-Pr) CH₂C(O)NMe(s-Bu) CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et)CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr) CH(Me)C(O)NH(n-Bu)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) C(Me)₂C(O)NH(Me) C(Me)₂C(O)NH(Et)C(Me)₂C(O)NH(n-Pr) C(Me)₂C(O)NH(i-Pr) (Me)₂C(O)NH(n-Bu)C(Me)₂C(O)NH(i-Bu) C(Me)₂C(O)NH(s-Bu) CH₂C(O)N(Me)CH₂CH₂FCH₂C(O)N(Me)CH₂CH₂Cl CH₂C(O)N(Me)CH₂CHF₂ CH₂C(O)N(Me)CH₂CF₃CH₂C(O)N(Me)CH₂CH₂CH₂F CH₂C(O)N(Me)CH₂CH₂CF₃ CH₂C(O)N(Me)CH₂CF₂CF₃CH₂C(O)N(Me)CH(Me)CF₃ CH₂C(O)N(Me)CH(CF₃)₂ CH₂C(O)N(Me)C(Me)₂CF₃CH(Me)C(O)N(Me)CH₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂Cl CH(Me)C(O)N(Me)CH₂CHF₂CH(Me)C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)(CH₂)₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂CF₃CH(Me)C(O)N(Me)CH₂CF₂CF₃ CH(Me)C(O)N(Me)CH(Me)CF₃CH(Me)C(O)N(Me)CH(CF₃)₂ CH(Me)C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)N(Me)CH₂CH₂FC(Me)₂C(O)N(Me)CH₂CH₂Cl C(Me)₂C(O)N(Me)CH₂CHF₂ C(Me)₂C(O)N(Me)CH₂CF₃C(Me)₂C(O)N(Me)CH₂CH₂CH₂F C(Me)₂C(O)N(Me)CH₂CH₂CF₃C(Me)₂C(O)N(Me)CH₂CF₂CF₃ C(Me)₂C(O)N(Me)CH(Me)CF₃C(Me)₂C(O)N(Me)CH(CF₃)₂ C(Me)₂C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)NHCH(Me)CF₃C(Me)₂C(O)NHCH(CF₃)₂ C(Me)₂C(O)NHC(Me)₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)CF₃C(Me)₂C(O)NH(CH₂)₂CF₂CF₃ C(Me)₂C(O)NHCH₂(CF₂)₂CF₃C(Me)₂C(O)NHCH(i-Pr)CF₃ CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) R¹ isOCH₂CF₃, R³ is Cl CH₂CH₂OH CH₂CH₂OMe CH₂CH₂OEt CH₂CH₂O(i-Pr) CH₂CH(Me)OHCH₂CH(CF₃)OH CH₂C(Me)₂OH CH₂C(CF₃)(Me)OH CH(Me)CH₂OH C(Me)₂CH₂OHCH(Et)CH₂OH CH(i-Pr)CH₂OH CH(i-Bu)CH₂OH CH(Me)CH(CF₃)OH CH₂CH₂CH₂OHCH₂CH₂CH₂OMe CH₂CH₂CH₂OEt CH₂CH₂CH(CF₃)OH CH(Me)CH₂CH₂OH CH₂CH(Me)CH₂OHCH₂C(Me)₂CH₂OH CH₂CH₂CH(Me)OH CH₂CH₂C(Me)₂OH CH₂CH₂SMe CH₂CH₂SEtCH₂CH₂S(n-Pr) CH₂CH₂S(i-Pr) CH₂CH₂S(i-Bu) CH₂CH(Me)SMe CH₂CH(CF₃)SMeCH₂C(Me)₂SMe CH(Me)CH₂SMe C(Me)₂CH₂SMe CH(Et)CH₂SMe CH(i-Pr)CH₂SMeCH(i-Bu)CH₂SMe CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂CH(Me)SMeCH₂CH₂CH(CF₃)SMe CH(Me)CH₂CH₂SMe CH(Et)CH₂CH₂SMe CH₂CH(Me)CH₂SMeCH₂C(Me)₂CH₂SMe CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr)CH₂CH₂S(O)(i-Pr) CH₂CH₂S(O)(i-Bu) CH₂CH(Me)S(O)Me CH₂CH(CF₃)S(O)MeCH₂C(Me)₂S(O)Me CH(Me)CH₂S(O)Me CH(Et)CH₂S(O)Me CH(i-Bu)CH₂S(O)MeCH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)Et CH₂CH₂CH₂S(O)(i-Bu) CH₂CH₂CH(Me)S(O)MeCH₂CH₂CH(CF₃)S(O)Me CH(Me)CH₂CH₂S(O)Me CH(Et)CH₂CH₂S(O)MeCH₂CH(Me)CH₂S(O)Me CH₂C(Me)₂CH₂S(O)Me CH₂(2-pyridinyl) CH₂CH₂SO₂MeCH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂SO₂(i-Pr) CH₂CH(Me)SO₂MeCH₂CH(CF₃)SO₂Me CH₂C(Me)₂SO₂Me CH(Me)CH₂SO₂Me C(Me)₂CH₂SO₂MeCH(Et)CH₂SO₂Me CH(i-Pr)CH₂SO₂Me CH(i-Bu)CH₂SO₂Me CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂CH₂CH(Me)SO₂Me CH₂CH₂CH(CF₃)SO₂Me CH(Me)CH₂CH₂SO₂MeCH(Et)CH₂CH₂SO₂Me CH₂CH(Me)CH₂SO₂Me CH₂C(Me)₂CH₂SO₂Me CH₂C(O)NHCH₂CH₂FCH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃ CH₂C(O)NHCH₂CH(Me)CH₂C(O)NHCH₂C(Me)₂F CH₂C(O)NH(CH₂)₂CH₂F CH₂C(O)NHCH₂CH₂CF₃CH₂C(O)NHCH₂CHFCF₃ CH₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NHCH(Me)CF₃CH₂C(O)NHCH(CF₃)₂ CH₂C(O)NHC(Me)₂CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH₂C(O)NH(CH₂)₂CF₂CF₃ CH₂C(O)NHCH₂(CF₂)₂CF₃ CH(Me)C(O)NHCH₂CH₂FCH(Me)C(O)NHCH₂CH₂Cl CH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃CH(Me)C(O)NHCH₂CH(Me)F CH(Me)C(O)NHCH₂C(Me)₂F CH(Me)C(O)NH(CH₂)₂CH₂FCH(Me)C(O)NHCH₂CH₂CF₃ CH(Me)C(O)NHCH₂CHFCF₃ CH(Me)C(O)NHCH₂CF₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH(CF₃)₂ CH(Me)C(O)NHC(Me)₂CF₃CH(Me)C(O)NHCH₂CH(Me)CF₃ CH(Me)C(O)NH(CH₂)₂CF₂CF₃CH(Me)C(O)NHCH₂(CF₂)₂CF₃ C(Me)₂C(O)NHCH₂CH₂F C(Me)₂C(O)NHCH₂CH₂ClC(Me)₂C(O)NHCH₂CHF₂ C(Me)₂C(O)NHCH₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)FC(Me)₂C(O)NHCH₂C(Me)₂F C(Me)₂C(O)NH(CH₂)₂CH₂F C(Me)₂C(O)NHCH₂CH₂CF₃C(Me)₂C(O)NHCH₂CHFCF₃ C(Me)₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂(4-thiazolyl) CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(n-Bu) CH₂C(O)NH(i-Bu)CH₂C(O)NH(s-Bu) CH₂C(O)NMe₂ CH₂C(O)NMe(Et) CH₂C(O)NEt₂ CH₂C(O)NMe(n-Pr)CH₂C(O)NMe(i-Pr) CH₂C(O)NMe(s-Bu) CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et)CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr) CH(Me)C(O)NH(n-Bu)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) C(Me)₂C(O)NH(Me) C(Me)₂C(O)NH(Et)C(Me)₂C(O)NH(n-Pr) C(Me)₂C(O)NH(i-Pr) (Me)₂C(O)NH(n-Bu)C(Me)₂C(O)NH(i-Bu) C(Me)₂C(O)NH(s-Bu) CH₂C(O)N(Me)CH₂CH₂FCH₂C(O)N(Me)CH₂CH₂Cl CH₂C(O)N(Me)CH₂CHF₂ CH₂C(O)N(Me)CH₂CF₃CH₂C(O)N(Me)CH₂CH₂CH₂F CH₂C(O)N(Me)CH₂CH₂CF₃ CH₂C(O)N(Me)CH₂CF₂CF₃CH₂C(O)N(Me)CH(Me)CF₃ CH₂C(O)N(Me)CH(CF₃)₂ CH₂C(O)N(Me)C(Me)₂CF₃CH(Me)C(O)N(Me)CH₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂Cl CH(Me)C(O)N(Me)CH₂CHF₂CH(Me)C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)(CH₂)₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂CF₃CH(Me)C(O)N(Me)CH₂CF₂CF₃ CH(Me)C(O)N(Me)CH(Me)CF₃CH(Me)C(O)N(Me)CH(CF₃)₂ CH(Me)C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)N(Me)CH₂CH₂FC(Me)₂C(O)N(Me)CH₂CH₂Cl C(Me)₂C(O)N(Me)CH₂CHF₂ C(Me)₂C(O)N(Me)CH₂CF₃C(Me)₂C(O)N(Me)CH₂CH₂CH₂F C(Me)₂C(O)N(Me)CH₂CH₂CF₃C(Me)₂C(O)N(Me)CH₂CF₂CF₃ C(Me)₂C(O)N(Me)CH(Me)CF₃C(Me)₂C(O)N(Me)CH(CF₃)₂ C(Me)₂C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)NHCH(Me)CF₃C(Me)₂C(O)NHCH(CF₃)₂ C(Me)₂C(O)NHC(Me)₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)CF₃C(Me)₂C(O)NH(CH₂)₂CF₂CF₃ C(Me)₂C(O)NHCH₂(CF₂)₂CF₃C(Me)₂C(O)NHCH(i-Pr)CF₃ CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) R¹ isOCH₂CF₃, R³ is Br CH₂CH₂OH CH₂CH₂OMe CH₂CH₂OEt CH₂CH₂O(i-Pr) CH₂CH(Me)OHCH₂CH(CF₃)OH CH₂C(Me)₂OH CH₂C(CF₃)(Me)OH CH(Me)CH₂OH C(Me)₂CH₂OHCH(Et)CH₂OH CH(i-Pr)CH₂OH CH(i-Bu)CH₂OH CH(Me)CH(CF₃)OH CH₂CH₂CH₂OHCH₂CH₂CH₂OMe CH₂CH₂CH₂OEt CH₂CH₂CH(CF₃)OH CH(Me)CH₂CH₂OH CH₂CH(Me)CH₂OHCH₂C(Me)₂CH₂OH CH₂CH₂CH(Me)OH CH₂CH₂C(Me)₂OH CH₂CH₂SMe CH₂CH₂SEtCH₂CH₂S(n-Pr) CH₂CH₂S(i-Pr) CH₂CH₂S(i-Bu) CH₂CH(Me)SMe CH₂CH(CF₃)SMeCH₂C(Me)₂SMe CH(Me)CH₂SMe C(Me)₂CH₂SMe CH(Et)CH₂SMe CH(i-Pr)CH₂SMeCH(i-Bu)CH₂SMe CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂CH(Me)SMeCH₂CH₂CH(CF₃)SMe CH(Me)CH₂CH₂SMe CH(Et)CH₂CH₂SMe CH₂CH(Me)CH₂SMeCH₂C(Me)₂CH₂SMe CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr)CH₂CH₂S(O)(i-Pr) CH₂CH₂S(O)(i-Bu) CH₂CH(Me)S(O)Me CH₂CH(CF₃)S(O)MeCH₂C(Me)₂S(O)Me CH(Me)CH₂S(O)Me CH(Et)CH₂S(O)Me CH(i-Bu)CH₂S(O)MeCH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)Et CH₂CH₂CH₂S(O)(i-Bu) CH₂CH₂CH(Me)S(O)MeCH₂CH₂CH(CF₃)S(O)Me CH(Me)CH₂CH₂S(O)Me CH(Et)CH₂CH₂S(O)MeCH₂CH(Me)CH₂S(O)Me CH₂C(Me)₂CH₂S(O)Me CH₂(2-pyridinyl) CH₂CH₂SO₂MeCH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂SO₂(i-Pr) CH₂CH(Me)SO₂MeCH₂CH(CF₃)SO₂Me CH₂C(Me)₂SO₂Me CH(Me)CH₂SO₂Me C(Me)₂CH₂SO₂MeCH(Et)CH₂SO₂Me CH(i-Pr)CH₂SO₂Me CH(i-Bu)CH₂SO₂Me CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂CH₂CH(Me)SO₂Me CH₂CH₂CH(CF₃)SO₂Me CH(Me)CH₂CH₂SO₂MeCH(Et)CH₂CH₂SO₂Me CH₂CH(Me)CH₂SO₂Me CH₂C(Me)₂CH₂SO₂Me CH₂C(O)NHCH₂CH₂FCH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃ CH₂C(O)NHCH₂CH(Me)CH₂C(O)NHCH₂C(Me)₂F CH₂C(O)NH(CH₂)₂CH₂F CH₂C(O)NHCH₂CH₂CF₃CH₂C(O)NHCH₂CHFCF₃ CH₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NHCH(Me)CF₃CH₂C(O)NHCH(CF₃)₂ CH₂C(O)NHC(Me)₂CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH₂C(O)NH(CH₂)₂CF₂CF₃ CH₂C(O)NHCH₂(CF₂)₂CF₃ CH(Me)C(O)NHCH₂CH₂FCH(Me)C(O)NHCH₂CH₂Cl CH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃CH(Me)C(O)NHCH₂CH(Me)F CH(Me)C(O)NHCH₂C(Me)₂F CH(Me)C(O)NH(CH₂)₂CH₂FCH(Me)C(O)NHCH₂CH₂CF₃ CH(Me)C(O)NHCH₂CHFCF₃ CH(Me)C(O)NHCH₂CF₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH(CF₃)₂ CH(Me)C(O)NHC(Me)₂CF₃CH(Me)C(O)NHCH₂CH(Me)CF₃ CH(Me)C(O)NH(CH₂)₂CF₂CF₃CH(Me)C(O)NHCH₂(CF₂)₂CF₃ C(Me)₂C(O)NHCH₂CH₂F C(Me)₂C(O)NHCH₂CH₂ClC(Me)₂C(O)NHCH₂CHF₂ C(Me)₂C(O)NHCH₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)FC(Me)₂C(O)NHCH₂C(Me)₂F C(Me)₂C(O)NH(CH₂)₂CH₂F C(Me)₂C(O)NHCH₂CH₂CF₃C(Me)₂C(O)NHCH₂CHFCF₃ C(Me)₂C(O)NHCH₂CF₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂(4-thiazolyl) CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(n-Bu) CH₂C(O)NH(i-Bu)CH₂C(O)NH(s-Bu) CH₂C(O)NMe₂ CH₂C(O)NMe(Et) CH₂C(O)NEt₂ CH₂C(O)NMe(n-Pr)CH₂C(O)NMe(i-Pr) CH₂C(O)NMe(s-Bu) CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et)CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr) CH(Me)C(O)NH(n-Bu)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) C(Me)₂C(O)NH(Me) C(Me)₂C(O)NH(Et)C(Me)₂C(O)NH(n-Pr) C(Me)₂C(O)NH(i-Pr) (Me)₂C(O)NH(n-Bu)C(Me)₂C(O)NH(i-Bu) C(Me)₂C(O)NH(s-Bu) CH₂C(O)N(Me)CH₂CH₂FCH₂C(O)N(Me)CH₂CH₂Cl CH₂C(O)N(Me)CH₂CHF₂ CH₂C(O)N(Me)CH₂CF₃CH₂C(O)N(Me)CH₂CH₂CH₂F CH₂C(O)N(Me)CH₂CH₂CF₃ CH₂C(O)N(Me)CH₂CF₂CF₃CH₂C(O)N(Me)CH(Me)CF₃ CH₂C(O)N(Me)CH(CF₃)₂ CH₂C(O)N(Me)C(Me)₂CF₃CH(Me)C(O)N(Me)CH₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂Cl CH(Me)C(O)N(Me)CH₂CHF₂CH(Me)C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)(CH₂)₂CH₂F CH(Me)C(O)N(Me)CH₂CH₂CF₃CH(Me)C(O)N(Me)CH₂CF₂CF₃ CH(Me)C(O)N(Me)CH(Me)CF₃CH(Me)C(O)N(Me)CH(CF₃)₂ CH(Me)C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)N(Me)CH₂CH₂FC(Me)₂C(O)N(Me)CH₂CH₂Cl C(Me)₂C(O)N(Me)CH₂CHF₂ C(Me)₂C(O)N(Me)CH₂CF₃C(Me)₂C(O)N(Me)CH₂CH₂CH₂F C(Me)₂C(O)N(Me)CH₂CH₂CF₃C(Me)₂C(O)N(Me)CH₂CF₂CF₃ C(Me)₂C(O)N(Me)CH(Me)CF₃C(Me)₂C(O)N(Me)CH(CF₃)₂ C(Me)₂C(O)N(Me)C(Me)₂CF₃ C(Me)₂C(O)NHCH(Me)CF₃C(Me)₂C(O)NHCH(CF₃)₂ C(Me)₂C(O)NHC(Me)₂CF₃ C(Me)₂C(O)NHCH₂CH(Me)CF₃C(Me)₂C(O)NH(CH₂)₂CF₂CF₃ C(Me)₂C(O)NHCH₂(CF₂)₂CF₃C(Me)₂C(O)NHCH(i-Pr)CF₃ CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr)

TABLE 4

R⁶ R¹ is Cl, R³ is Cl CH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMeCH₂CH₂CH₂SEt CH₂CH₂S(O)Me CH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)MeCH₂CH₂CH₂S(O)Et CH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂MeCH₂CH₂CH₂SO₂Et CH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et)CH₂C(O)NH(n-Pr) CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu)CH(Me)C(O)NH(Me) CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is Br, R³ is BrCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is CF₃, R³ is HCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is CF₃, R³ is FCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is CF₃, R³ is ClCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is CF₃, R³ is BrCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is CF₃, R³ is CF₃CH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is OCF₃, R³ is ClCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is OCH₂CF₃, R³ is FCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is OCH₂CF₃, R³ is ClCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃ R¹ is OCH₂CF₃, R³ is BrCH₂CH₂SMe CH₂CH₂SEt CH₂CH₂S(n-Pr) CH₂CH₂CH₂SMe CH₂CH₂CH₂SEt CH₂CH₂S(O)MeCH₂CH₂S(O)Et CH₂CH₂S(O)(n-Pr) CH₂CH₂CH₂S(O)Me CH₂CH₂CH₂S(O)EtCH₂CH₂SO₂Me CH₂CH₂SO₂Et CH₂CH₂SO₂(n-Pr) CH₂CH₂CH₂SO₂Me CH₂CH₂CH₂SO₂EtCH₂(2-pyridinyl) CH₂C(O)NH₂ CH₂C(O)NH(Me) CH₂C(O)NH(Et) CH₂C(O)NH(n-Pr)CH₂C(O)NH(i-Pr) CH₂C(O)NH(i-Bu) CH₂C(O)NH(s-Bu) CH(Me)C(O)NH(Me)CH(Me)C(O)NH(Et) CH(Me)C(O)NH(n-Pr) CH(Me)C(O)NH(i-Pr)CH(Me)C(O)NH(i-Bu) CH(Me)C(O)NH(s-Bu) CH₂(4-thiazolyl)CH₂C(O)N(Me)CH₂CF₃ CH(Me)C(O)N(Me)CH₂CF₃ CH₂C(O)NH(c-Pr)CH₂C(O)NH(CH₂—c-Pr) CH₂C(O)NHCH₂CH₂Cl CH₂C(O)NHCH₂CHF₂ CH₂C(O)NHCH₂CF₃CH₂C(O)NHCH₂CH₂CF₃ CH₂C(O)NHCH(Me)CF₃ CH₂C(O)NHCH₂CH(Me)CF₃CH(Me)C(O)NH(c-Pr) CH(Me)C(O)NH(CH₂—c-Pr) CH(Me)C(O)NHCH₂CH₂ClCH(Me)C(O)NHCH₂CHF₂ CH(Me)C(O)NHCH₂CF₃ CH(Me)C(O)NHCH₂CH₂CF₃CH(Me)C(O)NHCH(Me)CF₃ CH(Me)C(O)NHCH₂CH(Me)CF₃

Compositions of Formula 1 compounds may also contain formulationauxiliaries and additives, known to those skilled in the art asformulation aids (some of which may be considered to also function assolid diluents, liquid diluents or surfactants). Such formulationauxiliaries and additives may control: pH (buffers), foaming duringprocessing (antifoams such polyorganosiloxanes), sedimentation of activeingredients (suspending agents), viscosity (thixotropic thickeners),in-container microbial growth (antimicrobials), product freezing(antifreezes), color (dyes/pigment dispersions), wash-off (film formersor stickers), evaporation (evaporation retardants), and otherformulation attributes. Film formers include, for example, polyvinylacetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinylacetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers andwaxes. Examples of formulation auxiliaries and additives include thoselisted in McCutcheon's Volume 2: Functional Materials, annualInternational and North American editions published by McCutcheon'sDivision, The Manufacturing Confectioner Publishing Co.; and PCTPublication WO 03/024222.

Of note is the present method using a combination of a compound ofFormula 1 with at least one other parasitic invertebrate pest controlactive ingredient. Of particular note is such a method where the otherparasitic invertebrate pest control active ingredient has a differentsite of action from the compound of Formula 1. In certain instances, acombination with at least one other parasitic invertebrate pest controlactive ingredient having a similar spectrum of control but a differentsite of action will be particularly advantageous for resistancemanagement. Thus, a composition comprising a compound of Formula 1useful in the present method can further comprise a biologicallyeffective amount of at least one additional parasitic invertebrate pestcontrol active ingredient having a similar spectrum of control but adifferent site of action.

The compounds of Formula 1 can be applied without other adjuvants, butmost often application will be of a formulation comprising one or moreactive ingredients with suitable carriers, diluents, and surfactants andpossibly in combination with a food depending on the contemplated enduse. One method of application involves spraying a water dispersion orrefined oil solution of a compound of Formula 1. Combinations with sprayoils, spray oil concentrations, spreader stickers, adjuvants, othersolvents, and synergists such as piperonyl butoxide often enhancecompound efficacy. Such sprays can be applied from spray containers suchas a can, a bottle or other container, either by means of a pump or byreleasing it from a pressurized container, e.g., a pressurized aerosolspray can. Such spray compositions can take various forms, for example,sprays, mists, foams, fumes or fog. Such spray compositions thus canfurther comprise propellants, foaming agents, etc. as the case may be.Of note is a spray composition comprising a biologically effectiveamount of a compound or a composition of Formula 1 and a carrier. Oneembodiment of such a spray composition comprises a biologicallyeffective amount of a compound or a composition of Formula 1 and apropellant. Representative propellants include, but are not limited to,methane, ethane, propane, butane, isobutane, butene, pentane,isopentane, neopentane, pentene, hydrofluorocarbons,chlorofluorocarbons, dimethyl ether, and mixtures of the foregoing. Ofnote is a spray composition (and a method utilizing such a spraycomposition dispensed from a spray container) used to control at leastone parasitic invertebrate pest selected from the group consisting ofmosquitoes, black flies, stable flies, deer flies, horse flies, wasps,yellow jackets, hornets, ticks, spiders, ants, gnats, and the like,including individually or in combinations.

The controlling of animal parasites includes controlling externalparasites that are parasitic to the surface of the body of the hostanimal (e.g., shoulders, armpits, abdomen, inner part of the thighs) andinternal parasites that are parasitic to the inside of the body of thehost animal (e.g., stomach, intestine, lung, veins, under the skin,lymphatic tissue). External parasitic or disease transmitting pestsinclude, for example, chiggers, ticks, lice, mosquitoes, flies, mitesand fleas. Internal parasites include heartworms, hookworms andhelminths. Compounds and compositions of Formula 1 are particularlysuitable for combating external parasitic pests. Compounds andcompositions of Formula 1 are suitable for systemic and/or non-systemiccontrol of infestation or infection by parasites on animals.

Compounds and compositions of Formula 1 are suitable for combatingparasitic invertebrate pests that infest animal subjects including thosein the wild, livestock and agricultural working animals. Livestock isthe term used to refer (singularly or plurally) to a domesticated animalintentionally reared in an agricultural setting to make produce such asfood or fiber, or for its labor; examples of livestock include cattle,sheep, goats, horses, pigs, donkeys, camels, buffalo, rabbits, hens,turkeys, ducks and geese (e.g., raised for meat, milk, butter, eggs,fur, leather, feathers and/or wool). By combating parasites, fatalitiesand performance reduction (in terms of meat, milk, wool, skins, eggs,etc.) are reduced, so that applying a composition comprising a compoundof Formula 1 allows more economic and simple husbandry of animals.

Compounds and compositions of Formula 1 are especially suitable forcombating parasitic invertebrate pests that infest companion animals andpets (e.g., dogs, cats, pet birds and aquarium fish), research andexperimental animals (e.g., hamsters, guinea pigs, rats and mice), aswell as animals raised for/in zoos, wild habitats and/or circuses.

In an embodiment of this invention, the animal is preferably avertebrate, and more preferably a mammal, avian or fish. In a particularembodiment, the animal subject is a mammal (including great apes, suchas humans). Other mammalian subjects include primates (e.g., monkeys),bovine (e.g., cattle or dairy cows), porcine (e.g., hogs or pigs), ovine(e.g., goats or sheep), equine (e.g., horses), canine (e.g., dogs),feline (e.g., house cats), camels, deer, donkeys, buffalos, antelopes,rabbits, and rodents (e.g., guinea pigs, squirrels, rats, mice, gerbils,and hamsters). Avians include Anatidae (swans, ducks and geese),Columbidae (e.g., doves and pigeons), Phasianidae (e.g., partridges,grouse and turkeys), Thesienidae (e.g., domestic chickens), Psittacines(e.g., parakeets, macaws, and parrots), game birds, and ratites (e.g.,ostriches).

Birds treated or protected by the compounds of Formula 1 can beassociated with either commercial or noncommercial aviculture. Theseinclude Anatidae, such as swans, geese, and ducks, Columbidae, such asdoves and domestic pigeons, Phasianidae, such as partridge, grouse andturkeys, Thesienidae, such as domestic chickens, and Psittacines, suchas parakeets, macaws and parrots raised for the pet or collector market,among others.

For purposes of the present invention, the term “fish” shall beunderstood to include without limitation, the Teleosti grouping of fish,i.e., teleosts. Both the Salmoniformes order (which includes theSalmonidae family) and the Perciformes order (which includes theCentrarchidae family) are contained within the Teleosti grouping.Examples of potential fish recipients include the Salmonidae,Serranidae, Sparidae, Cichlidae, and Centrarchidae, among others.

Other animals are also contemplated to benefit from the inventivemethods, including marsupials (such as kangaroos), reptiles (such asfarmed turtles), and other economically important domestic animals forwhich the inventive methods are safe and effective in treating orpreventing parasite infection or infestation.

Examples of parasitic invertebrate pests controlled by administering apesticidally effective amount of a compound of Formula 1 to an animal tobe protected include ectoparasites (arthropods, acarines, etc.) andendoparasites (helminths, e.g., nematodes, trematodes, cestodes,acanthocephalans, etc.).

The disease or group of diseases described generally as helminthiasis isdue to infection of an animal host with parasitic worms known ashelminths. The term ‘helminths’ is meant to include nematodes,trematodes, cestodes and acanthocephalans. Helminthiasis is a prevalentand serious economic problem with domesticated animals such as swine,sheep, horses, cattle, goats, dogs, cats and poultry.

Among the helminths, the group of worms described as nematodes causeswidespread and at times serious infection in various species of animals.Nematodes that are contemplated to be treated by the compounds of thisinvention and by the inventive methods include, without limitation, thefollowing genera: Acanthocheilonema, Aelurostrongylus, Ancylostoma,Angiostrongylus, Ascaridia, Ascaris, Brugia, Bunostomum, Capillaria,Chabertia, Cooperia, Crenosoma, Dictyocaulus, Dioctophyme, Dipetalonema,Diphyllobothrium, Dirofilaria, Dracunculus, Enterobius, Filaroides,Haemonchus, Heterakis, Lagochilascaris, Loa, Mansonella, Muellerius,Necator, Nematodirus, Oesophagostomum, Ostertagia, Oxyuris, Parafilaria,Parascaris, Physaloptera, Protostrongylus, Setaria, Spirocerca,Stephanofilaria, Strongyloides, Strongylus, Thelazia, Toxascaris,Toxocara, Trichinella, Trichonema, Trichostrongylus, Trichuris,Uncinaria and Wuchereria.

Of the above, the most common genera of nematodes infecting the animalsreferred to above are Haemonchus, Trichostrongylus, Ostertagia,Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia,Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis,Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris andParascaris. Certain of these, such as Nematodirus, Cooperia andOesophagostomum attack primarily the intestinal tract while others, suchas Haemonchus and Ostertagia, are more prevalent in the stomach whileothers such as Dictyocaulus are found in the lungs. Still otherparasites may be located in other tissues such as the heart and bloodvessels, subcutaneous and lymphatic tissue and the like.

Trematodes that are contemplated to be treated by the compounds of thisinvention and by the inventive methods include, without limitation, thefollowing genera: Alaria, Fasciola, Nanophyetus, Opisthorchis,Paragonimus and Schistosoma.

Cestodes that are contemplated to be treated by the compounds of thisinvention and by the inventive methods include, without limitation, thefollowing genera: Diphyllobothrium, Diplydium, Spirometra and Taenia.

The most common genera of parasites of the gastrointestinal tract ofhumans are Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella,Capillaria, Trichuris and Enterobius. Other medically important generaof parasites which are found in the blood or other tissues and organsoutside the gastrointestinal tract are the filarial worms such asWuchereria, Brugia, Onchocerca and Loa, as well as Dracunculus and extraintestinal stages of the intestinal worms Strongyloides and Trichinella.

Numerous other helminth genera and species are known to the art, and arealso contemplated to be treated by the compounds of Formula 1. These areenumerated in great detail in Textbook of Veterinary ClinicalParasitology, Volume 1, Helminths, E. J. L. Soulsby, F. A. Davis Co.,Philadelphia, Pa.; Helminths, Arthropods and Protozoa, (6^(th) Editionof Monnig's Veterinary Helminthology and Entomology), E. J. L. Soulsby,The Williams and Wilkins Co., Baltimore, Md.

The compounds of Formula 1 are effective against a number of animalectoparasites (e.g., arthropod ectoparasites of mammals and birds).

Insect and acarine pests include, e.g., biting insects such as flies andmosquitoes, mites, ticks, lice, fleas, true bugs, parasitic maggots, andthe like.

Adult flies include, e.g., the horn fly or Haematobia irritans, thehorse fly or Tabanus spp., the stable fly or Stomoxys calcitrans, theblack fly or Simulium spp., the deer fly or Chrysops spp., the louse flyor Melophagus ovinus, and the tsetse fly or Glossina spp. Parasitic flymaggots include, e.g., the bot fly (Oestrus ovis and Cuterebra spp.),the blow fly or Phaenicia spp., the screwworm or Cochliomyiahominivorax, the cattle grub or Hypoderma spp., the fleeceworm and theGastrophilus of horses. Mosquitoes include, for example, Culex spp.,Anopheles spp. and Aedes spp.

Mites include Mesostigmata spp. e.g., mesostigmatids such as the chickenmite, Dermanyssus gallinae; itch or scab mites such as Sarcoptidae spp.for example, Sarcoptes scabiei; mange mites such as Psoroptidae spp.including Chorioptes bovis and Psoroptes ovis; chiggers e.g.,Trombiculidae spp. for example the North American chigger, Trombiculaalfreddugesi.

Ticks include, e.g., soft-bodied ticks including Argasidae spp. forexample Argas spp. and Ornithodoros spp.; hard-bodied ticks includingIxodidae spp., for example Rhipicephalus sanguineus, Dermacentorvariabilis, Dermacentor andersoni, Amblyomma americanum, Ixodesscapularis and other Rhipicephalus spp. (including the former Boophilusgenera).

Lice include, e.g., sucking lice, e.g., Menopon spp. and Bovicola spp.;biting lice, e.g., Haematopinus spp., Linognathus spp. and Solenopotesspp.

Fleas include, e.g., Ctenocephalides spp., such as dog flea(Ctenocephalides canis) and cat flea (Ctenocephalides felis); Xenopsyllaspp. such as oriental rat flea (Xenopsylla cheopis); and Pulex spp. suchas human flea (Pulex irritans).

True bugs include, e.g., Cimicidae or e.g., the common bed bug (Cimexlectularius); Triatominae spp. including triatomid bugs also known askissing bugs; for example Rhodnius prolixus and Triatoma spp.

Generally, flies, fleas, lice, mosquitoes, gnats, mites, ticks andhelminths cause tremendous losses to the livestock and companion animalsectors. Arthropod parasites also are a nuisance to humans and canvector disease-causing organisms in humans and animals.

Numerous other parasitic invertebrate pests are known to the art, andare also contemplated to be treated by the compounds of Formula 1. Theseare enumerated in great detail in Medical and Veterinary Entomology, D.S. Kettle, John Wiley & Sons, New York and Toronto; Control of ArthropodPests of Livestock: A Review of Technology, R. O. Drummand, J. E.George, and S. E. Kunz, CRC Press, Boca Raton, Fla.

In particular, the compounds of Formula 1 are especially effectiveagainst ectoparasites including Stomoxys calcitrans (stable fly); tickssuch as Ixodes spp., Boophilus spp., Rhipicephalus spp., Amblyomma spp.,Dermacentor spp., Hyalomma spp. and Haemaphysalis spp.; and fleas suchas Ctenocephalides felis (cat flea) and Ctenocephalides canis (dogflea).

The compounds of Formula 1 may also be effective against ectoparasitesincluding: flies such as Haematobia (Lyperosia) irritans (horn fly),Simulium spp. (blackfly), Glossina spp. (tsetse flies), Hydrotaeairritans (head fly), Musca autumnalis (face fly), Musca domestica (housefly), Morellia simplex (sweat fly), Tabanus spp. (horse fly), Hypodermabovis, Hypoderma lineatum, Lucilia sericata, Lucilia cuprina (greenblowfly), Calliphora spp. (blowfly), Protophormia spp., Oestrus ovis(nasal botfly), Culicoides spp. (midges), Hippobosca equine,Gastrophilus intestinalis, Gastrophilus haemorrhoidalis and Gastrophilusnasalis; lice such as Bovicola (Damalinia) bovis, Bovicola equi,Haematopinus asini, Felicola subrostratus, Heterodoxus spiniger,Lignonathus setosus and Trichodectes canis; keds such as Melophagusovinus; and mites such as Psoroptes spp., Sarcoptes scabei, Chorioptesbovis, Demodex equi, Cheyletiella spp., Notoedres cati, Trombicula spp.and Otodectes cyanotis (ear mites).

Other biologically active compounds or agents may be administered at thesame or different times as the compounds of Formula 1. Such compounds,for example, may be useful adjuncts in Formula 1 compositions for thepresent method. As noted below, such biologically active compounds maybe included in the composition of Formula 1. Such biologically activecompounds for use in the present invention include the organophosphatepesticides. This class of pesticides has very broad activity asinsecticides and, in certain instances, anthelminitic activity.Organophosphate pesticides include, e.g., dicrotophos, terbufos,dimethoate, diazinon, disulfoton, trichlorfon, azinphos-methyl,chlorpyrifos, malathion, oxydemeton-methyl, methamidophos, acephate,ethyl parathion, methyl parathion, mevinphos, phorate, carbofenthion andphosalone. Compositions of Formula 1 compounds for the present methodare also comtemplated to include carbamate-type pesticides, including,e.g., carbaryl, carbofuran, aldicarb, molinate, methomyl, carbofuran,etc., as well as combinations with the organochlorine type pesticides.Compositions of Formula 1 compounds are further contemplated to includecombinations with biological pesticides, including repellents, thepyrethrins (as well as synthetic variations thereof, e.g., allethrin,resmethrin, permethrin, tralomethrin), and nicotine, that is oftenemployed as an acaricide. Other contemplated combinations are withmiscellaneous pesticides including: Bacillus thuringiensis,chlorobenzilate, formamidines (e.g., amitraz), copper compounds (e.g.,copper hydroxide and cupric oxychloride sulfate), cyfluthrin,cypermethrin, dicofol, endosulfan, esfenvalerate, fenvalerate,lambda-cyhalothrin, methoxychlor and sulfur.

Of note are additional biologically active compounds or agents selectedfrom art-known anthelmintics, such as, for example, avermectins (e.g.,ivermectin, moxidectin, milbemycin), benzimidazoles (e.g., albendazole,triclabendazole), salicylanilides (e.g., closantel, oxyclozanide),substituted phenols (e.g., nitroxynil), pyrimidines (e.g., pyrantel),imidazothiazoles (e.g., levamisole) and praziquantel.

Other biologically active compounds or agents useful in the Formula 1compositions for the present method can be selected from Insect GrowthRegulators (IGRs) and Juvenile Hormone Analogues (JHAs) such asdiflubenzuron, triflumuron, fluazuron, cyromazine, methoprene, etc.,thereby providing both initial and sustained control of parasites (atall stages of insect development, including eggs) on the animal subject,as well as within the environment of the animal subject.

Of note are biologically active compounds or agents useful in theFormula 1 compositions for the present method selected from theavermectin class of antiparasitic compounds. As stated above, theavermectin family of compounds includes very potent antiparasitic agentsknown to be useful against a broad spectrum of endoparasites andectoparasites in mammals.

A preferred compound for use within the scope of the present inventionis ivermectin. Ivermectin is a semi-synthetic derivative of avermectinand is generally produced as a mixture of at least 80%22,23-dihydroavermectin B_(1a) and less than 20% 22,23-dihydroavermectinB_(1b). Ivermectin is disclosed in U.S. Pat. No. 4,199,569.

Abamectin is an avermectin that is disclosed as avermectin B_(1a)/B_(1b)in U.S. Pat. No. 4,310,519. Abamectin contains at least 80% ofavermectin B_(1a) and not more than 20% of avermectin B_(1b).

Another preferred avermectin is doramectin, also known as25-cyclohexyl-avermectin B₁. The structure and preparation of doramectinis disclosed in U.S. Pat. No. 5,089,480.

Another preferred avermectin is moxidectin. Moxidectin, also known asLL-F28249 alpha, is known from U.S. Pat. No. 4,916,154.

Another preferred avermectin is selamectin. Selamectin is25-cyclohexyl-25-de(1-methylpropyl)-5-deoxy-22,23-dihydro-5-(hydroxyimino)-avermectinB₁ monosaccharide.

Milbemycin, or B41, is a substance which is isolated from thefermentation broth of a milbemycin-producing strain of Streptomyces. Themicroorganism, the fermentation conditions and the isolation proceduresare described in U.S. Pat. Nos. 3,950,360 and 3,984,564.

Emamectin (4″-deoxy-4″-epi-methylaminoavermectin B₁), which can beprepared as described in U.S. Pat. Nos. 5,288,710 and 5,399,717, is amixture of two homologues, 4″-deoxy-4″-epi-methylaminoavermectin B_(1a)and 4″-deoxy-4″-epi-methylaminoavermectin B_(1b). Preferably, a salt ofemamectin is used. Non-limiting examples of salts of emamectin which maybe used in the present invention include the salts described in U.S.Pat. No. 5,288,710, e.g., salts derived from benzoic acid, substitutedbenzoic acid, benzenesulfonic acid, citric acid, phosphoric acid,tartaric acid, maleic acid, and the like. Most preferably, the emamectinsalt used in the present invention is emamectin benzoate.

Eprinomectin is chemically known as4″-epi-acetylamino-4″-deoxy-avermectin Eprinomectin was specificallydeveloped to be used in all cattle classes and age groups. It was thefirst avermectin to show broad-spectrum activity against both endo- andectoparasites while also leaving minimal residues in meat and milk. Ithas the additional advantage of being highly potent when deliveredtopically.

The Formula 1 compositions for the present method optionally comprisecombinations of one or more of the following antiparasite compounds:imidazo[1,2-b]pyridazine compounds as described by U.S. PatentApplication Publication No. 2005/0182059 A1; 1-(4-mono anddi-halomethylsulphonylphenyl)-2-acylamino-3-fluoropropanol compounds, asdescribed by U.S. Pat. No. 7,361,689; trifluoromethanesulfonanilideoxime ether derivatives, as described by U.S. Pat. No. 7,312,248; andn-[(phenyloxy)phenyl]-1,1,1-trifluoromethanesulfonamide andn-[(phenylsulfanyl)phenyl]-1,1,1-trifluoromethanesulfonamidederivatives, as described by PCT Patent Application Publication WO2006/135648.

The Formula 1 compositions may also further comprise a flukicide.Suitable flukicides include, for example, triclabendazole, fenbendazole,albendazole, clorsulon and oxibendazole. It will be appreciated that theabove combinations may further include combinations of antibiotic,antiparasitic and anti-fluke active compounds.

In addition to the above combinations, it is also contemplated toprovide Formula 1 compositions, as described herein for the presentmethod, with other animal health remedies such as trace elements,anti-inflammatories, anti-infectives, hormones, dermatologicalpreparations, including antiseptics and disinfectants, andimmunobiologicals such as vaccines and antisera for the prevention ofdisease.

For example, such antinfectives include one or more antibiotics that areoptionally co-administered during treatment using the inventive methods,e.g., in a combined composition and/or in separate dosage forms.Art-known antibiotics suitable for this purpose include, for example,those listed herein below.

One useful antibiotic is florfenicol, also known asD-(threo)-1-(4-methylsulfonylphenyl)chloroacetamido-3-fluoro-1-propanol.Another preferred antibiotic compound isD-(threo)-1-(4-methylsulfonylphenyl)-2-difluoroacetamido-3-fluoro-1-propanol.Another useful antibiotic is thiamphenicol. Processes for themanufacture of these antibiotic compounds, and intermediates useful insuch processes, are described in U.S. Pat. No. 431,857; 4,582,918;4,973,750; 4,876,352; 5,227,494; 4,743,700; 5,567,844; 5,105,009;5,382,673; 5,352,832; and 5,663,361. Other florfenicol analogs and/orprodrugs have been disclosed and such analogs also can be used in thecompositions and methods of the present invention (see e.g., U.S. Pat.Nos. 7,041,670 and 7,153,842).

Another useful antibiotic compound is tilmicosin. Tilmicosin is amacrolide antibiotic that is chemically defined as20-dihydro-20-deoxy-20-(cis-3,5-dimethylpiperidin-1-yl)-desmycosin andis disclosed in U.S. Pat. No. 4,820,695.

Another useful antibiotic for use in the present invention istulathromycin. Tulathromycin may be prepared in accordance with theprocedures set forth in U.S. Pat. No. 6,825,327.

Further antibiotics for use in the present invention include thecephalosporins such as, for example, ceftiofur, cefquinome, etc. Theconcentration of the cephalosporin in the formulation of the presentinvention optionally varies between about 1 mg/mL to 500 mg/mL.

Another useful antibiotic includes the fluoroquinolones, such as, forexample, enrofloxacin, danofloxacin, difloxacin, orbifloxacin andmarbofloxacin. In the case of enrofloxacin, it may be administered in aconcentration of about 100 mg/mL. Danofloxacin may be present in aconcentration of about 180 mg/mL.

Other useful macrolide antibiotics include compounds from the class ofketolides, or, more specifically, the azalides. Such compounds aredescribed in, for example, U.S. Pat. Nos. 6,514,945; 6,472,371;6,270,768; 6,437,151; 6,271,255; 6,239,12; 5,958,888; 6,339,063; and6,054,434.

Other useful antibiotics include the tetracyclines, particularlychlortetracycline and oxytetracycline. Other antibiotics may includeβ-lactams such as penicillins, e.g., penicillin, ampicillin,amoxicillin, or a combination of amoxicillin with clavulanic acid orother beta lactamase inhibitors.

Treatments of the invention are by conventional means such as by enteraladministration in the form of, for example, tablets, capsules, drinks,drenching preparations, granulates, pastes, boli, feed-throughprocedures, or suppositories; or by parenteral administration, such as,for example, by injection (including intramuscular, subcutaneous,intravenous, intraperitoneal) or implants; or by nasal administration.

The compounds of Formula 1 may be administered in a controlled releaseform, for example in subcutaneous or orally adminstered slow releaseformulations.

Typically a parasiticidal composition according to the present inventioncomprises a mixture of a compound of Formula 1, an N-oxide or a saltthereof, with one or more pharmaceutically or veterinarily acceptablecarriers comprising excipients and auxiliaries selected with regard tothe intended route of administration (e.g., oral or parenteraladministration such as injection) and in accordance with standardpractice. In addition, a suitable carrier is selected on the basis ofcompatibility with the one or more active ingredients in thecomposition, including such considerations as stability relative to pHand moisture content. Therefore of note is a composition for protectingan animal from an invertebrate parasitic pest comprising a parasiticallyeffective amount of a compound of Formula 1 and at least one carrier.

For parenteral administration including intravenous, intramuscular andsubcutaneous injection, a compound of Formula 1 can be formulated insuspension, solution or emulsion in oily or aqueous vehicles, and maycontain adjuncts such as suspending, stabilizing and/or dispersingagents. The compounds of Formula 1 may also be formulated for bolusinjection or continuous infusion. Pharmaceutical compositions forinjection include aqueous solutions of water-soluble forms of activeingredients (e.g., a salt of an active compound), preferably inphysiologically compatible buffers containing other excipients orauxiliaries as are known in the art of pharmaceutical formulation.Additionally, suspensions of the active compounds may be prepared in alipophilic vehicle. Suitable lipophilic vehicles include fatty oils suchas sesame oil, synthetic fatty acid esters such as ethyl oleate andtriglycerides, or materials such as liposomes. Aqueous injectionsuspensions may contain substances that increase the viscosity of thesuspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers. Alternatively, theactive ingredient may be in powder form for constitution with a suitablevehicle, e.g., sterile, pyrogen-free water, before use.

In addition to the formulations described supra, the compounds ofFormula 1 may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation (for example,subcutaneously or intramuscularly) or by intramuscular or subcutaneousinjection. The compounds of Formula 1 may be formulated for this routeof administration with suitable polymeric or hydrophobic materials (forinstance, in an emulsion with a pharmacologically acceptable oil), withion exchange resins, or as a sparingly soluble derivative such as,without limitation, a sparingly soluble salt.

For administration by inhalation, the compounds of Formula 1 can bedelivered in the form of an aerosol spray using a pressurized pack or anebulizer and a suitable propellant, e.g., without limitation,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane or carbon dioxide. In the case of apressurized aerosol, the dosage unit may be controlled by providing avalve to deliver a metered amount. Capsules and cartridges of, forexample, gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Compounds of Formula 1 have been discovered to have surprisinglyfavorable pharmacokinetic and pharmacodynamic properties providingsystemic availability from oral administration and ingestion. Thereforeafter ingestion by the animal to be protected, parasiticidally effectiveconcentrations of compounds of Formula 1 in the bloodstream protect thetreated animal from blood-sucking pests such as fleas, ticks and lice.Therefore of note is a composition for protecting an animal from aninvertebrate parasite pest in a form for oral administration (i.e.comprising, in addition to a parasiticidally effective amount of acompound of Formula 1, one or more carriers selected from binders andfillers suitable for oral administration and feed concentrate carriers).

For oral administration in the form of solutions (the most readilyavailable form for absorption), emulsions, suspensions, pastes, gels,capsules, tablets, boluses, powders, granules, rumen-retention andfeed/water/lick blocks, a compound of Formula 1 can be formulated withbinders/fillers known in the art to be suitable for oral administrationcompositions, such as sugars and sugar derivatives (e.g., lactose,sucrose, mannitol, sorbitol), starch (e.g., maize starch, wheat starch,rice starch, potato starch), cellulose and derivatives (e.g.,methylcellulose, carboxymethylcellulose, ethylhydroxycellulose), proteinderivatives (e.g., zein, gelatin), and synthetic polymers (e.g.,polyvinyl alcohol, polyvinylpyrrolidone). If desired, lubricants (e.g.,magnesium stearate), disintegrating agents (e.g., cross-linkedpolyvinylpyrrolidinone, agar, alginic acid) and dyes or pigments can beadded. Pastes and gels often also contain adhesives (e.g., acacia,alginic acid, bentonite, cellulose, xanthan gum, colloidal magnesiumaluminum silicate) to aid in keeping the composition in contact with theoral cavity and not being easily ejected.

A preferred embodiment is a composition of the present method formulatedinto a chewable and/or edible product (e.g., a chewable treat or edibletablet). Such a product would ideally have a taste, texture and/or aromafavored by the animal to be protected so as to facilitate oraladministration of the compound of Formula 1.

If the parasiticidal compositions are in the form of feed concentrates,the carrier is typically selected from high-performance feed, feedcereals or protein concentrates. Such feed concentrate-containingcompositions can, in addition to the parasiticidal active ingredients,comprise additives promoting animal health or growth, improving qualityof meat from animals for slaughter or otherwise useful to animalhusbandry. These additives can include, for example, vitamins,antibiotics, chemotherapeutics, bacteriostats, fungistats, coccidiostatsand hormones.

The compounds of Formula 1 may also be formulated in rectal compositionssuch as suppositories or retention enemas, using, e.g., conventionalsuppository bases such as cocoa butter or other glycerides.

The formulations for the method of this invention may include anantioxidant, such as BHT (butylated hydroxytoluene). The antioxidant isgenerally present in amounts of at 0.1-5% (wt/vol). Some of theformulations require a solubilizer, such as oleic acid, to dissolve theactive agent, particularly if spinosad is included. Common spreadingagents used in these pour-on formulations include isopropyl myristate,isopropyl palmitate, caprylic/capric acid esters of saturated C₁₂-C₁₈fatty alcohols, oleic acid, oleyl ester, ethyl oleate, triglycerides,silicone oils and dipropylene glycol methyl ether. The pour-onformulations for the method of this invention are prepared according toknown techniques. Where the pour-on is a solution, theparasiticide/insecticide is mixed with the carrier or vehicle, usingheat and stirring if required. Auxiliary or additional ingredients canbe added to the mixture of active agent and carrier, or they can bemixed with the active agent prior to the addition of the carrier.Pour-on formulations in the form of emulsions or suspensions aresimilarly prepared using known techniques.

Other delivery systems for relatively hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well-knownexamples of delivery vehicles or carriers for hydrophobic drugs. Inaddition, organic solvents such as dimethylsulfoxide may be used, ifneeded.

The rate of application required for effective parasitic invertebratepest control (i.e. “pesticidally effective amount”) will depend on suchfactors as the species of parasitic invertebrate pest to be controlled,the pest's life cycle, life stage, its size, location, time of year,host crop or animal, feeding behavior, mating behavior, ambientmoisture, temperature, and the like. One skilled in the art can easilydetermine the pesticidally effective amount necessary for the desiredlevel of parasitic invertebrate pest control.

In general for veterinary use, a compound or composition of Formula 1 isadministered in a pesticidally effective amount to an animal,particularly a homeothermic animal, to be protected from parasiticinvertebrate pests. A pesticidally effective amount is the amount ofactive ingredient needed to achieve an observable effect diminishing theoccurrence or activity of the target parasitic invertebrate pest. Oneskilled in the art will appreciate that the pesticidally effective dosecan vary for the various compounds and compositions useful for themethod of the present invention, the desired pesticidal effect andduration, the target parasitic invertebrate pest species, the animal tobe protected, the mode of application and the like, and the amountneeded to achieve a particular result can be determined through simpleexperimentation.

For oral or parenteral administration to animals, a dose of a compoundof the present invention administered at suitable intervals typicallyranges from about 0.01 mg/kg to about 100 mg/kg, and preferably fromabout 0.01 mg/kg to about 30 mg/kg of animal body weight.

Suitable intervals for the administration of compounds of the presentinvention to animals range from about daily to about yearly. Of note areadministration intervals ranging from about weekly to about once every 6months. Of particular note are monthly adminstration intervals (i.e.administering the compound to the animal once every month).

The following Tests demonstrate the control efficacy of compounds ofFormula 1 on specific pests. “Control efficacy” represents inhibition ofparasitic invertebrate pest development (including mortality) thatcauses significantly reduced feeding. The pest control protectionafforded by the compounds is not limited, however, to these species. SeeIndex Tables A and B for compound descriptions.

INDEX TABLE A

mp Cmpd R¹ R² R³ R⁴ R⁶ (° C.)  1 Cl H Cl CH₃ CH₂(2-pyridinyl) 67-69  2Cl H Cl CH₃ CH₂CH₂SCH₃ *  3 Cl H Cl CH₃ CH₂C(O)NHCH₂CF₃ *  4 Cl H Cl CH₃CH(CH₃)CH₂CH₂SCH₃ *  5 Cl H Cl CH₃ CH₂CH₂S(O)CH₃ *  6 Cl H Cl CH₃CH₂CH₂S(O)₂CH₃ *  7 Cl H Cl F CH₂(2-pyridinyl) *  8 Cl H Cl CH₃C(CH₃)₂CH₂SCH₃ *  9 Cl H Cl CH₃ (R)—CH(CH₃)C(O)NHCH₂CF₃ * 10 Cl H Cl CH₃C(CH₃)₂CH₂S(O)₂CH₃ * * See Index Table B for ¹H NMR data.

INDEX TABLE B Compound ¹H NMR Data (CDCl₃ solution unless indicatedotherwise)^(a) 2 δ 7.52 (m, 4H), 7.43 (m, 2H), 6.20 (br s, 1H), 4.08 (d,1H), 3.72 (d, 1H), 3.66 (m, 2H), 2.76 (t, 2H), 2.49 (s, 3H), 2.15 (s,3H). 3 δ 7.43-7.54 (m, 6H), 6.99 (br t, 1H), 6.75 (br t, 1H), 4.21 (d,2H), 4.08 (d, 1H), 3.95 (m, 2H), 3.70 (d, 1H), 2.47 (s, 3H). 4 δ 7.51(m, 4H), 7.43 (m, 2H), 5.74 (br d, 1H), 4.08 (d, 1H), 3.70 (d, 1H), 2.60(t, 2H), 2.47 (s, 3H), 2.13 (s, 3H), 1.3 (d, 3H). 5 δ 7.5 (m, 4H), 7.43(m, 1H), 7.0 (s, 1H), 6.84 (br s, 1H), 4.08 (d, 1H), 4.0 (m, 2H), 3.71(d, 1H), 3.17 (m, 1H), 2.91 (m, 1H), 2.68 (s, 3H), 2.49 (s, 3H). 6 δ 7.5(m, 4H), 7.43 (m, 2H), 7.0 (s, 1H), 6.58 (br s, 1H), 4.08 (d, 1H), 4.0(m, 2H), 3.71 (d, 1H), 3.36 (m, 2H), 3.0 (s, 3H), 2.49 (s, 3H). 7 δ 8.6(d, 1H), 8.2 (t, 1H), 8.1 (m, 1H), 7.7 (dt, 1H), 7.6-7.4 (m, 5H), 7.35(d, 1H), 7.25 (m, 1H), 4.8 (d, 2H), 4.1 (d, 1H), 3.7 (d, 1H). 8 δ 7.5(m, 4H), 7.43 (m, 2H), 5.75 (br s, 1H), 4.08 (d, 1H), 3.71 (d, 1H), 3.07(s, 2H), 2.48 (s, 3H), 2.18 (s, 3H), 1.51 (s, 6H). 9 δ 7.36-7.51 (m,7H), 6.85 (dd, 1H), 4.83 (m, 1H), 4.09 (d, 1H), 3.88 (m, 2H), 3.71 (d,1H), 2.40 (s, 3H), 1.51 (d, 3H). 10 δ 7.5 (m, 5H), 7.43 (s, 1H), 6.03(br s, 1H), 4.08 (d, 1H), 3.79 (s, 2H), 3.71 (d, 1H), 2.95 (s, 3H), 2.47(s, 3H), 1.69 (s, 6H). ^(a1)H NMR data are in ppm downfield fromtetramethylsilane. Couplings are designated by (s)-singlet, (d)-doublet,(t)-triplet, (q)-quartet, (dd)-doublet of doublets, (dt)-doublet oftriplets, (br)-broad peaks, (m)-multiplet.

Methods for preparing the compounds listed in Index Table A aredisclosed in PCT Patent Publication WO 2005/085216. To the extentnecessary to teach the methods of preparing the compounds Formula 1,(and only to the extent that they are not inconsistent with thedisclosure herein) this patent publication is herein incorporated byreference.

Biological Examples of the Invention Test A

For evaluating control of the cat flea (Ctenocephalides felis), a CD-1®mouse (about 30 g, male, obtained from Charles River Laboratories,Wilmington, Mass.) was orally dosed with a test compound in an amount of10 mg/kg solubilized in propylene glycol/glycerol formal (60:40). Twohours after oral administration of the test compound, approximately 8 to16 adult fleas were applied to each mouse. The fleas were then evaluatedfor mortality 48 hours after flea application to the mouse.

Of the compounds tested, the following compounds resulted in at least50% mortality: 1, 2, 3 and 4.

Test B

For evaluating control of the cat flea (Ctenocephalides felis), a CD-1®mouse (about 30 g, male, obtained from Charles River Laboratories,Wilmington, Mass.) was orally dosed with a test compound in an amount of10 mg/kg solubilized in propylene glycol/glycerol formal (60:40). Twentyfour hours after oral administration of the test compound, approximately8 to 16 adult fleas were applied to each mouse. The fleas were thenevaluated for mortality 48 hours after flea application to the mouse.

Of the compounds tested, the following compounds resulted in at least20% mortality: 1, 2 and 3. The following compounds resulted in at least50% mortality: 2 and 3.

Test C

For evaluating control of the cat flea (Ctenocephalides felis), a CD-1®mouse (about 30 g, male, obtained from Charles River Laboratories,Wilmington, Mass.) was subcutaneously dosed with a test compound in anamount of 10 mg/kg solubilized in propylene glycol/glycerol formal(60:40). Two hours after oral administration of the test compound,approximately 8 to 16 adult fleas were applied to each mouse. The fleaswere then evaluated for mortality 48 hours after flea application to themouse.

Of the compounds tested, the following compounds resulted in at least20% mortality: 1, 2 and 3. The following compounds resulted in at least50% mortality: 1 and 3.

Test D

For evaluating control of the cat flea (Ctenocephalides felis), a testcompound was solubilized in propylene glycol/glycerol formal (60:40) andthen diluted in bovine blood to a final test rate of 30 ppm. The treatedblood was placed in a tube, and the bottom of the tube was covered witha membrane. Approximately 10 adult cat fleas were allowed to feedthrough the membrane on the treated blood. The adult fleas were thenevaluated for mortality 72 hours later.

Of the compounds tested, the following compounds resulted in at least50% mortality: 1, 2, 3, 5, 6, 7, 8, 9 and 10.

What is claimed is:
 1. A method for protecting an animal from aparasitic invertebrate pest comprising orally or parenterallyadministering to the animal a pesticidally effective amount of acompound of Formula 1, an N-oxide or a salt thereof

wherein R¹ is halogen, C₁-C₃ haloalkyl or C₁-C₃ haloalkoxy; R² is H,halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl or cyano; R³ is H, halogen, C₁-C₃haloalkyl or C₁-C₃ haloalkoxy; R⁴ is halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl or C₁-C₃ haloalkoxy; R⁵ is H, CH₃, C₂-C₄ alkylcarbonyl, C₂-C₄haloalkylcarbonyl, C₂-C₅ alkoxycarbonyl or CH₂O(C₁-C₃ alkyl); R⁶ isC₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl or C₃-C₆ halocycloalkyl,each group substituted with one R⁷; or R⁶ is (CH₂)_(m)Q; Q is a 4- to6-membered saturated ring containing carbon atoms and one O or S(O)_(n)as ring members and optionally substituted with 1 or 2 R^(8a) and oneR^(8b); R⁷ is OR⁹, S(O)_(n)R¹⁰ or C(O)NR¹¹R¹²; or R⁷ is pyridine orthiazole, each optionally substituted with 1 or 2 R¹⁵; each R^(8a) isindependently halogen, cyano or C₁-C₂ alkyl; R^(8b) is OR⁹, S(O)_(n)R¹⁰or C(O)NR¹¹R¹²; R⁹ is H, CHO, C₂-C₄ alkylcarbonyl, C₂-C₄haloalkylcarbonyl or C₂-C₅ alkoxycarbonyl; or R⁹ is C₁-C₄ alkyl or C₁-C₄haloalkyl, each optionally substituted with one R¹³; or R⁹ is pyridineor thiazole, each optionally substituted with 1 or 2 R¹⁵; R¹⁰ is C₁-C₄alkyl or C₁-C₄ haloalkyl, each optionally substituted with one R¹³; orR¹⁰ is pyridine or thiazole, each optionally substituted with 1 or 2R¹⁵; R¹¹ is H, CHO, C₁-C₄ alkyl, C₁-C₄ haloalkyl, CH₂O(C₁-C₃ alkyl),C₂-C₄ alkylcarbonyl, C₂-C₄ haloalkylcarbonyl or C₂-C₅ alkoxycarbonyl;R¹² is C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₃-C₆ cycloalkyl, each optionallysubstituted with one R¹³; or R¹² is H, C₃-C₆ alkenyl, C₃-C₆ haloalkenyl,C₃-C₆ alkynyl or OR¹⁴; R¹³ is cyano, C₃-C₆ cycloalkyl, C₃-C₆halocycloalkyl, OH, OR¹⁴ or S(O)_(n)R¹⁶; or R¹³ is pyridine or thiazole,each optionally substituted with 1 or 2 R¹⁵; R¹⁴ is C₁-C₄ alkyl or C₁-C₄haloalkyl; each R¹⁵ is independently halogen, cyano, C₁-C₃ alkyl, C₁-C₃haloalkyl or C₁-C₃ haloalkoxy; R¹⁶ is C₁-C₄ alkyl or C₁-C₄ haloalkyl; mis 0 or 1; and n is 0, 1 or
 2. 2. The method of claim 1 wherein R⁴ is Clor CH₃; R⁵ is H; R⁶ is C₁-C₆ alkyl substituted with one R⁷; and R⁷ isOR⁹, S(O)_(n)R¹⁰ or C(O)NR¹¹R¹².
 3. The method of claim 2 wherein R¹ isCl, Br, CF₃, OCF₃ or OCH₂CF₃; R² is H; and R³ is H, F, Cl, Br or CF₃. 4.The method of claim 3 wherein R⁴ is CH₃; and R⁷ is C(O)NR¹¹R¹².
 5. Themethod of claim 4 wherein R¹ is CF₃; and R³ is Cl, Br or CF₃.
 6. Themethod of claim 4 wherein R¹¹ is H; and R¹² is C₁-C₄ alkyl or C₁-C₄haloalkyl.
 7. The method of claim 4 wherein R¹¹ is H; and R¹² iscyclopropyl or cyclopropylmethyl.
 8. The method of claim 1 wherein thepesticidally effective amount of a compound of Formula 1 is administeredorally.
 9. The method of claim 1 wherein the pesticidally effectiveamount of a compound of Formula 1 is administered parenterally.
 10. Themethod of claim 9 wherein the pesticidally effective amount of acompound of Formula 1 is administered by injection.
 11. The method ofclaim 1 wherein the animal to be protected is a mammal.
 12. The methodof claim 11 wherein the mammal to be protected is livestock.
 13. Themethod of claim 11 wherein the mammal to be protected is a canine. 14.The method of claim 11 wherein the mammal to be protected is a feline.15. The method of claim 1 wherein the parasitic invertebrate pest is anectoparasite.
 16. The method of claim 1 wherein the parasiticinvertebrate pest is an arthropod.
 17. The method of claim 1 wherein theparasitic invertebrate pest is a fly, mosquito, mite, tick, louse, flea,true bug or maggot.
 18. The method of claim 17 wherein the animal to beprotected is a cat or dog and the parasitic invertebrate pest is a flea,tick or mite.